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http://www.ncbi.nlm.nih.gov/pubmed/27246296 | 1. Hum Vaccin Immunother. 2016 Sep;12(9):2391-402. doi:
10.1080/21645515.2016.1183077. Epub 2016 May 31.
Effect of antipyretic analgesics on immune responses to vaccination.
Saleh E(1), Moody MA(2), Walter EB(3).
Author information:
(1)a Department of Pediatrics , Division of Pediatric Infectious Diseases, Duke
Clinical Vaccine Unit, Duke University School of Medicine , Durham , NC , USA.
(2)b Duke Human Vaccine Institute, Department of Pediatrics, Division of
Pediatric Infectious Diseases, Duke University School of Medicine , Durham , NC
, USA.
(3)c Duke Clinical Vaccine Unit, Department of Pediatrics, Divisions of Primary
Care and Pediatric Infectious Diseases, Duke University School of Medicine ,
Durham , NC , USA.
While antipyretic analgesics are widely used to ameliorate vaccine adverse
reactions, their use has been associated with blunted vaccine immune responses.
Our objective was to review literature evaluating the effect of antipyretic
analgesics on vaccine immune responses and to highlight potential underlying
mechanisms. Observational studies reporting on antipyretic use around the time
of immunization concluded that their use did not affect antibody responses. Only
few randomized clinical trials demonstrated blunted antibody response of unknown
clinical significance. This effect has only been noted following primary
vaccination with novel antigens and disappears following booster immunization.
The mechanism by which antipyretic analgesics reduce antibody response remains
unclear and not fully explained by COX enzyme inhibition. Recent work has
focused on the involvement of nuclear and subcellular signaling pathways. More
detailed immunological investigations and a systems biology approach are needed
to precisely define the impact and mechanism of antipyretic effects on vaccine
immune responses.
DOI: 10.1080/21645515.2016.1183077
PMCID: PMC5027726
PMID: 27246296 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36127354 | 1. NPJ Prim Care Respir Med. 2022 Sep 21;32(1):35. doi:
10.1038/s41533-022-00300-z.
The use of non-steroidal anti-inflammatory drugs (NSAIDs) in COVID-19.
Kushner P(1)(2), McCarberg BH(3), Grange L(4)(5), Kolosov A(6), Haveric AL(7),
Zucal V(8), Petruschke R(9), Bissonnette S(9).
Author information:
(1)Kushner Wellness Center, Los Angeles, CA, USA. pamkushner@hotmail.com.
(2)Department of Family Medicine, University of California, Irvine, CA, USA.
pamkushner@hotmail.com.
(3)Department of Family Medicine, University of California at San Diego School
of Medicine, San Diego, CA, USA.
(4)Rheumatology Department, Grenoble-Alpes University Hospital, Echirolles,
France.
(5)President of the French League Against Rheumatism (AFLAR), Paris, France.
(6)Medical Affairs, GSK Consumer Healthcare, Rochester Park, Singapore,
Singapore.
(7)Consumer Safety, GSK Consumer Healthcare, Nyon, Switzerland.
(8)Consumer Safety, GSK Consumer Healthcare, Warren, NJ, USA.
(9)Medical Affairs, GSK Consumer Healthcare, Warren, NJ, USA.
Early in the COVID-19 pandemic, anecdotal reports emerged suggesting
non-steroidal anti-inflammatory drugs (NSAIDs) may increase susceptibility to
infection and adversely impact clinical outcomes. This narrative literature
review (March 2020-July 2021) attempted to clarify the relationship between
NSAID use and COVID-19 outcomes related to disease susceptibility or severity.
Twenty-four relevant publications (covering 25 studies) reporting original
research data were identified; all were observational cohort studies, and eight
were described as retrospective. Overall, these studies are consistent in
showing that NSAIDs neither increase the likelihood of SARS-CoV-2 infection nor
worsen outcomes in patients with COVID-19. This is reflected in current
recommendations from major public health authorities across the world, which
support NSAID use for analgesic or antipyretic treatment during COVID-19. Thus,
there is no basis on which to restrict or prohibit use of these drugs by
consumers or patients to manage their health conditions and symptoms during the
pandemic.
© 2022. The Author(s).
DOI: 10.1038/s41533-022-00300-z
PMCID: PMC9489480
PMID: 36127354 [Indexed for MEDLINE]
Conflict of interest statement: P.K. is a speaker and an advisory board member
for GSK. B.H.M. is an advisor to Lilly, Scilex, and Averitas, a member of the
Speaker’s Bureau for Adapt and Scilex, and holds stocks in Johnson & Johnson.
L.G. is a member of the French board of GRAINS, which is supported by GSK. A.K.,
A.L.H., V.Z., R.P., and S.B. are current or former employees of GSK Consumer
Healthcare. |
http://www.ncbi.nlm.nih.gov/pubmed/36401022 | 1. Methods Mol Biol. 2023;2587:31-41. doi: 10.1007/978-1-0716-2772-3_2.
Viltolarsen: From Preclinical Studies to FDA Approval.
Roshmi RR(1), Yokota T(2)(3).
Author information:
(1)Department of Medical Genetics, Faculty of Medicine and Dentistry, University
of Alberta, Edmonton, Canada.
(2)Department of Medical Genetics, Faculty of Medicine and Dentistry, University
of Alberta, Edmonton, Canada. toshifum@ualberta.ca.
(3)The Friends of Garrett Cumming Research & Muscular Dystrophy Canada, HM
Toupin Neurological Science Research Chair, Edmonton, Canada.
toshifum@ualberta.ca.
Viltolarsen is a phosphorodiamidate morpholino antisense oligonucleotide (PMO)
designed to skip exon 53 of the DMD gene for the treatment of Duchenne muscular
dystrophy (DMD), one of the most common lethal genetic disorders characterized
by progressive degeneration of skeletal muscles and cardiomyopathy. It was
developed by Nippon Shinyaku in collaboration with the National Center of
Neurology and Psychiatry (NCNP) in Japan based on the preclinical studies
conducted in the DMD dog model at the NCNP. After showing hopeful results in
pre-clinical trials and several clinical trials across North America and Japan,
it received US Food and Drug Administration (FDA) approval for DMD in 2020.
Viltolarsen restores the reading frame of the DMD gene by skipping exon 53 and
produces a truncated but functional form of dystrophin. It can treat
approximately 8-10% of the DMD patient population. This paper aims to summarize
the development of viltolarsen from preclinical trials to clinical trials to,
finally, FDA approval, and discusses the challenges that come with fighting DMD
using antisense therapy.
© 2023. The Author(s), under exclusive license to Springer Science+Business
Media, LLC, part of Springer Nature.
DOI: 10.1007/978-1-0716-2772-3_2
PMID: 36401022 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24556385 | 1. Eur J Dermatol. 2014 Jan-Feb;24(1):28-34. doi: 10.1684/ejd.2013.2252.
Use of recombinant C1 inhibitor in patients with resistant or frequent attacks
of hereditary or acquired angioedema.
Manson AL(1), Dempster J(1), Grigoriadou S(1), Buckland MS(1), Longhurst HJ(1).
Author information:
(1)Department of Immunology, Barts Health NHS Trust, London E1 2ES, UK.
BACKGROUND: Conestat alfa (Ruconest, rhC1INH) is the first recombinant human C1
inhibitor protein (C1INH) for the treatment of acute attacks of hereditary
angioedema (HAE).
OBJECTIVE: To assess clinical experience of the first 11 adult patients who
received rhC1INH in clinical practice in the UK.
METHODS: Eleven patients (nine HAE type 1, one HAE type 2 and one acquired
angioedema with C1 inhibitor deficiency) received between one and six, mostly
self-administered, doses of rhC1INH for acute HAE attacks. They were asked to
record their time to first response and complete resolution following the
treatment. This cohort included our most severely affected and difficult to
treat patients.
RESULTS: In most cases, time to first improvement following rhC1INH and complete
resolution was recorded as comparable to their typical response to pdC1INH,
although 4/11 patients reported that the time to first improvement was much
quicker than their average pdC1INH response. Five of the 11 patients continued
with rhC1INH as their preferred rescue treatment. Of those who chose not to
continue the treatment, four reported a recurrence or early return of symptoms
with rhC1INH.
CONCLUSION: In our experience, rhC1INH is a beneficial treatment for patients
with preference for a C1INH that is not plasma derived and it is suitable for
home treatment. In some cases it demonstrates cost saving, especially for
heavier patients who require higher doses. In some patients rhC1INH may result
in faster resolution of symptoms. It may be associated with an early return of
symptoms in patients with exceptionally frequent attacks.
DOI: 10.1684/ejd.2013.2252
PMID: 24556385 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32453377 | 1. JAMA Neurol. 2020 Aug 1;77(8):982-991. doi: 10.1001/jamaneurol.2020.1264.
Safety, Tolerability, and Efficacy of Viltolarsen in Boys With Duchenne Muscular
Dystrophy Amenable to Exon 53 Skipping: A Phase 2 Randomized Clinical Trial.
Clemens PR(1)(2), Rao VK(3), Connolly AM(4), Harper AD(5), Mah JK(6), Smith
EC(7), McDonald CM(8), Zaidman CM(9), Morgenroth LP(10), Osaki H(11), Satou
Y(11), Yamashita T(11), Hoffman EP(12)(13); CINRG DNHS Investigators.
Author information:
(1)Department of Neurology, University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania.
(2)Department of Veterans Affairs Medical Center, Pittsburgh, Pennsylvania.
(3)Division of Neurology, Ann and Robert H. Lurie Children's Hospital of
Chicago, Chicago, Illinois.
(4)Division of Neurology, Nationwide Children's Hospital, The Ohio State
University College of Medicine, Columbus.
(5)Children's Hospital of Richmond at Virginia Commonwealth University,
Richmond.
(6)Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada.
(7)Division of Pediatric Neurology, Duke University Medical Center, Durham,
North Carolina.
(8)Department of Physical Medicine and Rehabilitation, Department of Pediatrics,
UC Davis Health, University of California, Davis, Sacramento.
(9)Department of Neurology, Washington University at St Louis, St Louis,
Missouri.
(10)Graduate School of Public Health, University of Pittsburgh, Pittsburgh,
Pennsylvania.
(11)NS Pharma, Paramus, New Jersey.
(12)AGADA BioSciences, Dalhousie University, Halifax, Nova Scotia, Canada.
(13)Department of Pharmaceutical Sciences, State University of New York at
Binghamton.
Erratum in
JAMA Neurol. 2020 Aug 1;77(8):1040. doi: 10.1001/jamaneurol.2020.2025.
IMPORTANCE: An unmet need remains for safe and efficacious treatments for
Duchenne muscular dystrophy (DMD). To date, there are limited agents available
that address the underlying cause of the disease.
OBJECTIVE: To evaluate the safety, tolerability, and efficacy of viltolarsen, a
novel antisense oligonucleotide, in participants with DMD amenable to exon 53
skipping.
DESIGN, SETTING, AND PARTICIPANTS: This phase 2 study was a 4-week randomized
clinical trial for safety followed by a 20-week open-label treatment period of
patients aged 4 to 9 years with DMD amenable to exon 53 skipping. To enroll 16
participants, with 8 participants in each of the 2 dose cohorts, 17 participants
were screened. Study enrollment occurred between December 16, 2016, and August
17, 2017, at sites in the US and Canada. Data were collected from December 2016
to February 2018, and data were analyzed from April 2018 to May 2019.
INTERVENTIONS: Participants received 40 mg/kg (low dose) or 80 mg/kg (high dose)
of viltolarsen administered by weekly intravenous infusion.
MAIN OUTCOMES AND MEASURES: Primary outcomes of the trial included safety,
tolerability, and de novo dystrophin protein production measured by Western blot
in participants' biceps muscles. Secondary outcomes included additional
assessments of dystrophin mRNA and protein production as well as clinical muscle
strength and function.
RESULTS: Of the 16 included boys with DMD, 15 (94%) were white, and the mean
(SD) age was 7.4 (1.8) years. After 20 to 24 weeks of treatment, significant
drug-induced dystrophin production was seen in both viltolarsen dose cohorts (40
mg/kg per week: mean [range] 5.7% [3.2-10.3] of normal; 80 mg/kg per week: mean
[range] 5.9% [1.1-14.4] of normal). Viltolarsen was well tolerated; no
treatment-emergent adverse events required dose reduction, interruption, or
discontinuation of the study drug. No serious adverse events or deaths occurred
during the study. Compared with 65 age-matched and treatment-matched natural
history controls, all 16 participants treated with viltolarsen showed
significant improvements in timed function tests from baseline, including time
to stand from supine (viltolarsen: -0.19 s; control: 0.66 s), time to run/walk
10 m (viltolarsen: 0.23 m/s; control: -0.04 m/s), and 6-minute walk test
(viltolarsen: 28.9 m; control: -65.3 m) at the week 25 visit.
CONCLUSIONS AND RELEVANCE: Systemic treatment of participants with DMD with
viltolarsen induced de novo dystrophin production, and clinical improvement of
timed function tests was observed.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02740972.
DOI: 10.1001/jamaneurol.2020.1264
PMCID: PMC7251505
PMID: 32453377 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of Interest Disclosures: Dr Clemens has
received grants from NS Pharma during the conduct of the study as well as grants
from Spark Therapeutics, Amicus Therapeutics, Sanofi Genzyme, ReveraGen
BioPharma, and TRiNDS and personal fees from Spark Therapeutics, UCB, Pfizer,
and Roche outside the submitted work. Dr Rao has received nonfinancial support
from Ann and Robert H. Lurie Children’s Hospital of Chicago during the conduct
of the study as well as personal fees from PTC Therapeutics and Sarepta
Therapeutics outside the submitted work. Dr Connelly has received grants from
the Washington University School of Medicine and TRiNDS during the conduct of
the study as well as grants from Sarepta Therapeutics and AveXis and personal
fees from Sarepta Therapeutics, AveXis, Genentech-Roche, Acceleron Pharma, and
Catabasis Pharmaceuticals outside the submitted work. Dr Harper has received
grants from NS Pharma, Italfarmaco, ReveraGen BioPharma, Catabasis
Pharmaceuticals, AveXis, CSL Behring, Teva Pharmaceutical Industries, National
Institutes of Health, and US Centers for Disease Control and Prevention. Dr Mah
has received grants from NS Pharma during the conduct of the study as well as
grants from PTC Therapeutics, Pfizer, Roche, Sarepta Therapeutics, Italfarmaco,
Novartis, Biogen, ReveraGen BioPharma, Catabasis Pharmaceuticals,
Sanofi-Genzyme, and Bristol-Myers Squibb outside the submitted work. Dr Smith
has received salary support from NS Pharma during the conduct of the study as
well as personal fees from Pfizer and Sarepta Therapeutics and salary support
from Pfizer and ReveraGen BioPharma outside the submitted work. Dr McDonald has
received grants from NS Pharma during the conduct of the study as well as
personal fees from Bristol-Myers Squibb, Astellas/Mitobridge, Cardero
Therapeutics, Capricor Therapeutics, Catabasis Pharmaceuticals, Eli Lilly and
Company, Epirium Bio, FibroGen, Halo Therapeutics, Italfarmaco, BioMarin
Pharmaceutical, Novartis, Pfizer, Prosensa, PTC Therapeutics, Santhera
Pharmaceuticals, and Sarepta Therapeutics outside the submitted work. Dr Zaidman
has received nonfinancial support from Biogen outside the submitted work. Ms
Morgenroth has received salary support from TRiNDS during the conduct of the
study. Mr Osaki and Dr Yamashita are employed by NS Pharma. Mr Satou is employed
by NS Pharma and has patent PCT/JP2011/070318 issued and licensed to Nippon
Shinyaku and the National Center of Neurology and Psychiatry and has patent
PCT/JP2019/026393 pending. Dr Hoffman has received grants from AGADA Biosciences
and TRiNDS during the conduct of the study and grants from ReveraGen BioPharma
outside the submitted work. |
http://www.ncbi.nlm.nih.gov/pubmed/34938127 | 1. Clin Pharmacol. 2021 Dec 16;13:235-242. doi: 10.2147/CPAA.S288842. eCollection
2021.
Pharmacological Profile of Viltolarsen for the Treatment of Duchenne Muscular
Dystrophy: A Japanese Experience.
Roshmi RR(1), Yokota T(1).
Author information:
(1)Department of Medical Genetics, University of Alberta, Edmonton, Alberta,
Canada.
Duchenne muscular dystrophy (DMD) is a fatal, X-linked recessive disorder
characterized by progressive muscle loss and cardiorespiratory complications.
Mutations in the DMD gene that eliminate the production of dystrophin protein
are the underlying causes of DMD. Viltolarsen is a drug of phosphorodiamidate
morpholino oligomer (PMO) chemistry, designed to skip exon 53 of the DMD gene.
It aims to produce truncated but partially functional dystrophin in DMD patients
and restore muscle function. Based on a preclinical study showing the ability of
antisense PMOs targeting the DMD gene to improve muscle function in a large
animal model, viltolarsen was developed by Nippon Shinyaku and the National
Center of Neurology and Psychiatry in Japan. Following clinical trials conducted
in Japan, Canada, and the United States showing significant improvements in
muscle function, viltolarsen was approved for medical use in Japan in March 2020
and the United States in August 2020, respectively. Viltolarsen is a
mutation-specific drug and will work for 8% of the persons with DMD who carry
mutations amenable to exon 53 skipping. This review summarizes the
pharmacological profile of viltolarsen, important clinical trials, and
challenges, focusing on the contribution of Japanese patients and researchers in
its development.
© 2021 Roshmi and Yokota.
DOI: 10.2147/CPAA.S288842
PMCID: PMC8688746
PMID: 34938127
Conflict of interest statement: TY is a co-founder and shareholder
of OligomicsTx Inc., which aims to commercialize antisense technology. The
authors report no other conflicts of interest in this work. |
http://www.ncbi.nlm.nih.gov/pubmed/35634851 | 1. J Neuromuscul Dis. 2022;9(4):493-501. doi: 10.3233/JND-220811.
Long-Term Functional Efficacy and Safety of Viltolarsen in Patients with
Duchenne Muscular Dystrophy.
Clemens PR(1)(2), Rao VK(3), Connolly AM(4), Harper AD(5), Mah JK(6), McDonald
CM(7), Smith EC(8), Zaidman CM(9), Nakagawa T(10); CINRG DNHS Investigators;
Hoffman EP(11).
Author information:
(1)Department of Neurology, University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania.
(2)Department of Veterans Affairs Medical Center, Pittsburgh, Pennsylvania.
(3)Division of Neurology, Ann and Robert H. Lurie Children's Hospital of
Chicago, Chicago, Illinois.
(4)Division of Neurology, Nationwide Children's Hospital, The Ohio State
University College of Medicine, Columbus, Ohio.
(5)Children's Hospital of Richmond at Virginia Commonwealth University,
Richmond, Virginia.
(6)Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada.
(7)Department of Physical Medicine and Rehabilitation, Department of Pediatrics,
UC Davis Health, University of California, Davis, Sacramento, California.
(8)Duke University Medical Center, Durham, North Carolina.
(9)Department of Neurology, Washington University at St Louis, St Louis,
Missouri.
(10)NS Pharma, Inc, Paramus, New Jersey.
(11)Department of Pharmaceutical Sciences, State University of New York at
Binghamton, Binghamton, New York.
BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare, genetic disease caused
by mutations in the DMD gene resulting in an absence of functional dystrophin
protein. Viltolarsen, an exon 53 skipping therapy, has been shown to increase
endogenous dystrophin levels. Herein, long-term (>2 years) functional outcomes
in viltolarsen treated patients were compared to a matched historical control
group.
OBJECTIVE: To evaluate long-term efficacy and safety of the anti-sense
oligonucleotide viltolarsen in the treatment of patients with DMD amenable to
exon 53 skipping therapy.
METHODS: This trial (NCT03167255) is the extension of a previously published
24-week trial in North America (NCT02740972) that examined dystrophin levels,
timed function tests compared to a matched historical control group (Cooperative
International Neuromuscular Research Group Duchenne Natural History Study, CINRG
DNHS), and safety in boys 4 to < 10 years (N = 16) with DMD amenable to exon 53
skipping who were treated with viltolarsen. Both groups were treated with
glucocorticoids. All 16 participants elected to enroll in this long-term trial
(up to 192 weeks) to continue evaluation of motor function and safety.
RESULTS: Time to stand from supine and time to run/walk 10 meters showed
stabilization from baseline through week 109 for viltolarsen-treated
participants whereas the historical control group showed decline (statistically
significant differences for multiple timepoints). Safety was similar to that
observed in the previous 24-week trial, which was predominantly mild. There have
been no treatment-related serious adverse events and no discontinuations.
CONCLUSIONS: Based on these results at over 2 years, viltolarsen can be a new
treatment option for patients with DMD amenable to exon 53 skipping.
DOI: 10.3233/JND-220811
PMCID: PMC9398057
PMID: 35634851 [Indexed for MEDLINE]
Conflict of interest statement: a. Dr Clemens has received grants from NS Pharma
during the conduct of the study as well as grants from Spark Therapeutics,
Amicus Therapeutics, Sanofi Genzyme, ReveraGen BioPharma, NIH, MDA, and TRiNDS
and personal fees from Epirium, outside the submitted work. b. Dr Rao has
received grants and personal fees from NS Pharma during the conduct of the study
and nonfinancial support from Ann and Robert H. Lurie Children’s Hospital of
Chicago during the conduct of the study as well as personal fees from Biogen,
Avexis/Novartis, Capricor, Regenxbio, Genentech-Roche, Scholar Rock, PTC
Therapeutics, Sarepta Therapeutics, France Foundation, and MDA outside the
submitted work. c. Dr Connolly has received grants from the Washington
University School of Medicine and TRiNDS during the conduct of the study as well
as grants from Sarepta Therapeutics, AveXis, and Fibrogen and personal fees from
Sarepta Therapeutics, Scholar Rock, Genentech-Roche, Dyne Therapeutics, and
Edgewise Therapeutics outside the submitted work. d. Dr Harper has received
grants from NS Pharma, Italfarmaco, ReveraGen BioPharma, Catabasis
Pharmaceuticals, Astellas Pharmaceuticals, MLBio, AveXis, CSL Behring, Teva
Pharmaceutical Industries, Novartis, National Institutes of Health, and US
Centers for Disease Control and Prevention. e. Dr Mah has received grants from
NS Pharma during the conduct of the study as well as personal fees from PTC
Therapeutics, Biogen and Roche and grants from PTC Therapeutics, Pfizer, Roche,
Sarepta Therapeutics, Italfarmaco, Novartis, Biogen, ReveraGen BioPharma,
Catabasis Pharmaceuticals, Sanofi-Genzyme, and Alberta Children’s Hospital
Foundation outside the submitted work. f. Dr McDonald has received grants from
NS Pharma during the conduct of the study as well as personal fees from Avidity
Biosciences, Astellas, Capricor Therapeutics, Catabasis Pharmaceuticals,
Edgewise Therapeutics, Entrada Therapeutics, Epirium Bio, FibroGen, Italfarmaco,
Pfizer, PTC Therapeutics, Roche, Santhera Pharmaceuticals, Solid Biosciences,
and Sarepta Therapeutics outside the submitted work. g. Dr Smith has received
personal fees from NS Pharma during the conduct of the study as well as personal
fees from Pfizer and Sarepta Therapeutics outside the submitted work. h. Dr
Zaidman has received grant support from Biogen and Novartis outside the
submitted work. i. Mr Nakagawa is an employee of NS Pharma, Inc. j. Dr Hoffman
has received fees from NS Pharma, holds stock and held oversight roles in AGADA
Biosciences and TRiNDS during the conduct of the study, and holds stock and has
management roles in ReveraGen BioPharma outside the submitted work. |
http://www.ncbi.nlm.nih.gov/pubmed/32519222 | 1. Drugs. 2020 Jul;80(10):1027-1031. doi: 10.1007/s40265-020-01339-3.
Viltolarsen: First Approval.
Dhillon S(1).
Author information:
(1)Springer Nature, Private Bag 65901, Mairangi Bay, Auckland, 0754, New
Zealand. dru@adis.com.
Viltolarsen (Viltepso® in Japan) is a phosphorodiamidate morpholino antisense
oligonucleotide being developed by Nippon Shinyaku, in collaboration with the
National Center of Neurology and Psychiatry (NCNP), for the treatment of
Duchenne muscular dystrophy (DMD). Viltolarsen binds to exon 53 of the
dystrophin mRNA precursor and restores the amino acid open-reading frame by
skipping exon 53, resulting in the production of a shortened dystrophin protein
that contains essential functional portions. In March 2020, intravenous
viltolarsen received its first global approval in Japan for the treatment of DMD
in patients with confirmed deletion of the dystrophin gene that is amenable to
exon 53 skipping. Viltolarsen is under regulatory review in the USA and clinical
trials continue in the USA, Canada and globally. This article summarizes the
milestones in the development of viltolarsen leading to the first approval for
DMD.
DOI: 10.1007/s40265-020-01339-3
PMID: 32519222 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31720560 | 1. Drugs Today (Barc). 2019 Oct;55(10):627-639. doi:
10.1358/dot.2019.55.10.3045038.
Viltolarsen for the treatment of Duchenne muscular dystrophy.
Roshmi RR(1), Yokota T(2).
Author information:
(1)Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada.
(2)Department of Medical Genetics, University of Alberta and The Friends of
Garrett Cumming Research and Muscular Dystrophy Canada, HM Toupin Neurological
Science Research Chair, Edmonton, AB, Canada. toshifum@ualberta.ca.
Duchenne muscular dystrophy is the most common lethal X-linked genetic disorder,
characterized by progressive muscle loss, with cardiac and respiratory
complications. It is caused by a lack of dystrophin protein due to mutations in
the DMD gene, which can disrupt the reading frame of the dystrophin primary
transcript. Antisense oligonucleotides such as phosphorodiamidate morpholino
oligomers (PMOs) can induce exon skipping during pre-mRNA splicing and restore
the reading frame of the DMD primary transcript. The resulting dystrophin
protein is internally deleted but partially functional. Viltolarsen, also known
as NS-065/NCNP-01, is a PMO developed through comprehensive sequence
optimization and is designed to skip exon 53 on the DMD primary transcript.
Exclusion of exon 53 from the DMD primary transcript can treat 8-10% of DMD
patients worldwide. This review paper summarizes the mechanism of action,
pharmacokinetics and safety of viltolarsen from preclinical and clinical trials.
Copyright 2019 Clarivate Analytics.
DOI: 10.1358/dot.2019.55.10.3045038
PMID: 31720560 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33285037 | 1. Ann Clin Transl Neurol. 2020 Dec;7(12):2393-2408. doi: 10.1002/acn3.51235.
Epub 2020 Dec 7.
Viltolarsen in Japanese Duchenne muscular dystrophy patients: A phase 1/2 study.
Komaki H(1), Takeshima Y(2), Matsumura T(3), Ozasa S(4), Funato M(5), Takeshita
E(6), Iwata Y(7), Yajima H(7), Egawa Y(8), Toramoto T(8), Tajima M(8), Takeda
S(9).
Author information:
(1)Translational Medical Center, National Center of Neurology and Psychiatry,
Kodaira, Tokyo, Japan.
(2)Department of Pediatrics, Hyogo College of Medicine, Nishinomiya, Hyogo,
Japan.
(3)Department of Neurology, National Hospital Organization Osaka Toneyama
Medical Center, Toyonaka, Osaka, Japan.
(4)Department of Pediatrics, Kumamoto University Hospital, Kumamoto, Kumamoto,
Japan.
(5)Department of Pediatrics, National Hospital Organization Nagara Medical
Center, Gifu, Japan.
(6)Department of Child Neurology, National Center of Neurology and Psychiatry,
National Center Hospital, Kodaira, Tokyo, Japan.
(7)Department of Rehabilitation, National Center of Neurology and Psychiatry,
National Center Hospital, Kodaira, Tokyo, Japan.
(8)Global Clinical Development Department, Nippon Shinyaku Co., Ltd., Kyoto,
Kyoto, Japan.
(9)National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
OBJECTIVE: The novel morpholino antisense oligonucleotide viltolarsen targets
exon 53 of the dystrophin gene, and could be an effective treatment for patients
with Duchenne muscular dystrophy (DMD). We investigated viltolarsen's ability to
induce dystrophin expression and examined its safety in DMD patients.
METHODS: In this open-label, multicenter, parallel-group, phase 1/2, exploratory
study, 16 ambulant and nonambulant males aged 5-12 years with DMD received
viltolarsen 40 or 80 mg/kg/week via intravenous infusion for 24 weeks. Primary
endpoints were dystrophin expression and exon 53 skipping levels.
RESULTS: In western blot analysis, mean changes in dystrophin expression (%
normal) from baseline to Weeks 12 and 24 were - 1.21 (P = 0.5136) and 1.46
(P = 0.1636), respectively, in the 40 mg/kg group, and 0.76 (P = 0.2367) and
4.81 (P = 0.0536), respectively, in the 80 mg/kg group. The increase in mean
dystrophin level at Weeks 12 and 24 was significant in the 80 mg/kg group
(2.78%; P = 0.0364). Patients receiving 80 mg/kg showed a higher mean exon 53
skipping level (42.4%) than those receiving 40 mg/kg (21.8%). All adverse events
were judged to be mild or moderate in intensity and none led to study
discontinuation.
INTERPRETATION: Treatment with viltolarsen 40 or 80 mg/kg elicited an increasing
trend in dystrophin expression and exon 53 skipping levels, and was safe and
well tolerated. The decline in motor function appeared less marked in patients
with higher dystrophin levels; this may warrant further investigation. This
study supports the potential clinical benefit of viltolarsen.
© 2020 The Authors. Annals of Clinical and Translational Neurology published by
Wiley Periodicals LLC on behalf of American Neurological Association.
DOI: 10.1002/acn3.51235
PMCID: PMC7732240
PMID: 33285037 [Indexed for MEDLINE]
Conflict of interest statement: H.K. has received grants from Taiho, Pfizer
Japan, Nippon Shinyaku, Daiichi Sankyo, Chugai, PTC Therapeutics; and personal
fees from Sarepta Therapeutics. Y.T. has received grants from Nippon Shinyaku;
and personal fees from Daiichi Sankyo and Biogen. T.M. has received grants from
Nippon Shinyaku. S.O. has received grants from Nippon Shinyaku, Biogen, and PTC
Therapeutics. M.F. has received grants from Nippon Shinyaku and Taiho. E.T. has
received grants from Taiho, Nippon Shinyaku, Daiichi Sankyo, and Takeda; and
personal fees from Pfizer Japan. Y.I. has received grants from Taiho, Nippon
Shinyaku, and Daiichi Sankyo; and personal fees from Astellas Pharma. H.Y. has
received grants from Taiho, Nippon Shinyaku, and Daiichi Sankyo; and personal
fees from Biogen. S.T. is an officer and board member of the National Center of
Neurology and Psychiatry; and has received grants from Nippon Shinyaku, Daiichi
Sankyo and The Noguchi Institute. Y.E., M.T., and T.T. are employees of Nippon
Shinyaku Co., Ltd. |
http://www.ncbi.nlm.nih.gov/pubmed/32483212 | 1. Gene Ther. 2020 Sep;27(9):407-416. doi: 10.1038/s41434-020-0156-6. Epub 2020
Jun 1.
Optimization of antisense-mediated exon skipping for Duchenne muscular
dystrophy.
Dzierlega K(1), Yokota T(2).
Author information:
(1)Department of Medical Genetics, University of Alberta Faculty of Medicine and
Dentistry, Edmonton, Alberta, Canada.
(2)Department of Medical Genetics, University of Alberta Faculty of Medicine and
Dentistry, Edmonton, Alberta, Canada. toshifum@ualberta.ca.
Duchenne muscular dystrophy (DMD) is one of the most common lethal
muscle-wasting disorders affecting young boys caused by mutations in the DMD
gene. Exon skipping has emerged as a promising therapy for DMD. Antisense
oligonucleotides (AONs) are designed to induce the skipping of exon(s), in order
to restore the reading frame, and therefore, allow for dystrophin expression.
Eteplirsen and golodirsen, AONs for DMD exons 51 and 53 skipping, have been
recently approved by the FDA. Viltolarsen, an AON for DMD exon 53 skipping, was
approved in Japan earlier this year. Although promising, the efficacy of
eteplirsen and AON sequence employed remain controversial. In addition, exon
skipping faces challenges including the applicability and delivery. This article
reviews and discusses exon skipping and the current advances being made in the
field, on drugs, multi-exon skipping, sequence design, and applicability. We
also discuss challenges and future directions that will facilitate the
development of exon skipping therapy.
DOI: 10.1038/s41434-020-0156-6
PMID: 32483212 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36401027 | 1. Methods Mol Biol. 2023;2587:125-139. doi: 10.1007/978-1-0716-2772-3_7.
Restoring Dystrophin Expression with Exon 44 and 53 Skipping in the DMD Gene in
Immortalized Myotubes.
Echigoya Y(1)(2), Yokota T(3)(4).
Author information:
(1)Laboratory of Biomedical Science, Department of Veterinary Medicine, College
of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa, Japan.
echigoya.yusuke@nihon-u.ac.jp.
(2)Nihon University Veterinary Research Center, Fujisawa, Kanagawa, Japan.
echigoya.yusuke@nihon-u.ac.jp.
(3)Department of Medical Genetics, Faculty of Medicine and Dentistry, University
of Alberta, Edmonton, AB, Canada.
(4)The Friends of Garrett Cumming Research & Muscular Dystrophy Canada, HM
Toupin Neurological Science Research Chair, Edmonton, AB, Canada.
Phosphorodiamidate morpholino oligomer (PMO)-mediated exon skipping is a
therapeutic approach that applies to many Duchenne muscular dystrophy (DMD)
patients harboring out-of-frame deletion mutations in the DMD gene. In
particular, PMOs for skipping exon 44 have been developing in clinical trials,
such as the drug NS-089/NCNP-02. Two exon 53 skipping PMOs, golodirsen and
viltolarsen, have received conditional approval for treating patients due to
their ability to restore dystrophin protein expression. Although promising,
further development of exon-skipping technology is needed for patients to have
more therapeutic benefit. This chapter describes evaluation methods of exon 44
and 53 skipping PMOs in immortalized DMD patient-derived skeletal muscle cells.
We introduce how to quantify exon-skipping efficiencies and dystrophin rescue
levels represented by RT-PCR and western blotting, respectively. The screening
methods using immortalized patient myotubes can serve to find exon-skipping PMO
drug candidates.
© 2023. The Author(s), under exclusive license to Springer Science+Business
Media, LLC, part of Springer Nature.
DOI: 10.1007/978-1-0716-2772-3_7
PMID: 36401027 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32947786 | 1. J Pers Med. 2020 Sep 16;10(3):129. doi: 10.3390/jpm10030129.
Molecular Diagnosis and Novel Therapies for Neuromuscular Diseases.
Maruyama R(1), Yokota T(1)(2).
Author information:
(1)Department of Medical Genetics, Faculty of Medicine and Dentistry, University
of Alberta, Edmonton, AB T6G 2H7, Canada.
(2)The Friends of Garrett Cumming Research & Muscular Dystrophy Canada, HM
Toupin Neurological Science Research Chair, Edmonton, AB T6G 2H7, Canada.
With the development of novel targeted therapies, including exon
skipping/inclusion and gene replacement therapy, the field of neuromuscular
diseases has drastically changed in the last several years. Until 2016, there
had been no FDA-approved drugs to treat Duchenne muscular dystrophy (DMD), the
most common muscular dystrophy. However, several new personalized therapies,
including antisense oligonucleotides eteplirsen for DMD exon 51 skipping and
golodirsen and viltolarsen for DMD exon 53 skipping, have been approved in the
last 4 years. We are witnessing the start of a therapeutic revolution in
neuromuscular diseases. However, the studies also made clear that these
therapies are still far from a cure. Personalized genetic medicine for
neuromuscular diseases faces several key challenges, including the difficulty of
obtaining appropriate cell and animal models and limited its applicability. This
Special Issue "Molecular Diagnosis and Novel Therapies for
Neuromuscular/Musculoskeletal Diseases" highlights key areas of research
progress that improve our understanding and the therapeutic outcomes of
neuromuscular diseases in the personalized medicine era.
DOI: 10.3390/jpm10030129
PMCID: PMC7564006
PMID: 32947786
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35911297 | 1. Cureus. 2022 Jun 25;14(6):e26316. doi: 10.7759/cureus.26316. eCollection 2022
Jun.
Cat-Eye Syndrome: A Report of Two Cases and Literature Review.
Gaspar NS(1), Rocha G(2), Grangeia A(3), Soares HC(2).
Author information:
(1)Pediatrics, Centro Hospitalar do Médio Tejo, Torres Novas, PRT.
(2)Neonatology, Centro Hospitalar Universitário de São João, Porto, PRT.
(3)Genetics, Centro Hospitalar Universitário de São João, Porto, PRT.
Cat-eye syndrome is a rare genetic disease that involves the proximal long (q)
arm of chromosome 22. The classic clinical triad includes coloboma of the iris,
ears, and anal malformations. This syndrome was named "cat eye" due to the
vertical coloboma of the iris. However, the spectrum of clinical manifestations
is variable, and the iris coloboma may be absent in 40-50% of cases. Association
with congenital heart disease is also frequent and its diagnosis should raise
suspicion of a genetic condition. We describe two cases of male infants affected
by the cat-eye syndrome, of which no one presented the classic clinical triad.
One of them had unpredictable complications that led to prolonged neonatal
intensive care unit stay. Although having distinct phenotypes, the diagnosis in
both cases was made through nonobstructive total anomalous pulmonary venous
return, anal imperforation, and craniofacial anomalies. Iris coloboma was an
important clue only in one of them. Prenatal diagnosis is a challenge, such that
a genetic study is essential for a final diagnosis in the absence of the classic
triad.
Copyright © 2022, Gaspar et al.
DOI: 10.7759/cureus.26316
PMCID: PMC9314234
PMID: 35911297
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/36076277 | 1. Ital J Pediatr. 2022 Sep 8;48(1):170. doi: 10.1186/s13052-022-01365-9.
Congenital hypopituitarism and multiple midline defects in a newborn with
non-familial Cat Eye syndrome.
Serra G(1), Giambrone C(2), Antona V(2), Cardella F(3), Carta M(2), Cimador
M(2), Corsello G(2), Giuffrè M(2), Insinga V(2), Maggio MC(3), Pensabene M(2),
Schierz IAM(2), Piro E(2).
Author information:
(1)Department of Health Promotion, Mother and Child Care, Internal Medicine and
Medical Specialties "G. D'Alessandro", University of Palermo, Palermo, Italy.
gregorio.serra@unipa.it.
(2)Department of Health Promotion, Mother and Child Care, Internal Medicine and
Medical Specialties "G. D'Alessandro", University of Palermo, Palermo, Italy.
(3)Pediatric Unit, Children's Hospital "G. Di Cristina", University of Palermo,
Palermo, Italy.
BACKGROUND: Cat eye syndrome (CES) is a rare chromosomal disease, with estimated
incidence of about 1 in 100,000 live newborns. The classic triad of iris
coloboma, anorectal malformations, and auricular abnormalities is present in 40%
of patients, and other congenital defects may also be observed. The typical
associated cytogenetic anomaly relies on an extra chromosome, derived from an
inverted duplication of short arm and proximal long arm of chromosome 22,
resulting in partial trisomy or tetrasomy of such regions (inv dup
22pter-22q11.2).
CASE PRESENTATION: We report on a full-term newborn, referred to us soon after
birth. Physical examination showed facial dysmorphisms, including hypertelorism,
down slanted palpebral fissures, and dysplastic ears with tragus hypoplasia and
pre-auricular pit. Ophthalmologic evaluation and heart ultrasound identified
left chorioretinal and iris coloboma and ostium secundum type atrial septal
defect, respectively. Based on the suspicion of cat eye syndrome, a standard
karyotype analysis was performed, and detected an extra small marker chromosome
confirming the CES diagnosis. The chromosomal abnormality was then defined by
array comparative genome hybridization (a-CGH, performed also in the parents),
which identified the size of the rearrangement (3 Mb), and its de novo
occurrence. Postnatally, our newborn presented with persistent hypoglycemia and
cholestatic jaundice. Endocrine tests revealed congenital hypothyroidism,
cortisol and growth hormone (GH) deficiencies, which were treated with
replacement therapies (levotiroxine and hydrocortisone). Brain magnetic
resonance imaging, later performed, showed aplasia of the anterior pituitary
gland, agenesis of the stalk and ectopic neurohypophysis, confirming the
congenital hypopituitarism diagnosis. She was discharged at 2 months of age, and
included in a multidisciplinary follow-up. She currently is 7 months old and
shows a severe global growth failure, and developmental delay. She started GH
replacement treatment, and continues oral hydrocortisone, along with
ursodeoxycholic acid and levothyroxine, allowing an adequate control of glycemic
and thyroid profiles as well as of cholestasis.
CONCLUSIONS: CES phenotypic spectrum is wide and highly variable. Our report
highlights how among the possible associated endocrine disorders, congenital
hypopituitarism may occur, leading to persistent hypoglycemia and cholestasis.
These patients should be promptly assessed for complete hormonal evaluations, in
addition to major malformations and midline anomalies. Early recognition of such
defects is necessary to decrease fatal events, as well as short and long-term
related adverse outcomes.
© 2022. The Author(s).
DOI: 10.1186/s13052-022-01365-9
PMCID: PMC9461219
PMID: 36076277 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no competing
interests. |
http://www.ncbi.nlm.nih.gov/pubmed/33405070 | 1. Drugs. 2021 Feb;81(2):277-282. doi: 10.1007/s40265-020-01463-0.
Lumasiran: First Approval.
Scott LJ(1), Keam SJ(2).
Author information:
(1)Springer Nature, Mairangi Bay, Private Bag 65901, Auckland, 0754, New
Zealand. dru@adis.com.
(2)Springer Nature, Mairangi Bay, Private Bag 65901, Auckland, 0754, New
Zealand.
Lumasiran (Oxlumo™) is a subcutaneously administered small interfering RNA
(siRNA) targeting the mRNA for hydroxyacid oxidase 1 gene (HAO1; encodes
glycolate oxidase) and was developed by Alnylam Pharmaceuticals for the
treatment of primary hyperoxaluria type 1 (PH1). By silencing the gene encoding
glycolate oxidase, lumasiran depletes glycolate oxidase and thereby inhibits the
synthesis of oxalate, which is the toxic metabolite that is directly associated
with the clinical manifestations of PH1. On 19 November 2020, lumasiran received
its first global approval in the EU for the treatment of PH1 in all age groups.
On 23 November 2020, lumasiran was approved in the USA for the treatment of
adult and paediatric patients with PH1. This article summarizes the milestones
in the development of lumasiran leading to this first approval.
DOI: 10.1007/s40265-020-01463-0
PMID: 33405070 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34154993 | 1. Drug Metab Dispos. 2022 Jun;50(6):781-797. doi: 10.1124/dmd.121.000428. Epub
2021 Jun 21.
The Nonclinical Disposition and Pharmacokinetic/Pharmacodynamic Properties of
N-Acetylgalactosamine-Conjugated Small Interfering RNA Are Highly Predictable
and Build Confidence in Translation to Human.
McDougall R(1), Ramsden D(1), Agarwal S(1), Agarwal S(1), Aluri K(1), Arciprete
M(1), Brown C(1), Castellanos-Rizaldos E(1), Charisse K(1), Chong S(1), Cichocki
J(1), Fitzgerald K(1), Goel V(1), Gu Y(1), Guenther D(1), Habtemariam B(1),
Jadhav V(1), Janas M(1), Jayaraman M(1), Kurz J(1), Li J(1), Liu J(1), Liu X(1),
Liou S(1), Maclauchlin C(1), Maier M(1), Manoharan M(1), Nair JK(1), Robbie
G(1), Schmidt K(1), Smith P(1), Theile C(1), Vaishnaw A(1), Waldron S(1), Xu
Y(1), Zhang X(1), Zlatev I(1), Wu JT(2).
Author information:
(1)Alnylam Pharmaceuticals, Cambridge, Massachusetts.
(2)Alnylam Pharmaceuticals, Cambridge, Massachusetts jtwu@alnylam.com.
Conjugation of oligonucleotide therapeutics, including small interfering RNAs
(siRNAs) or antisense oligonucleotides, to N-acetylgalactosamine (GalNAc)
ligands has become the primary strategy for hepatocyte-targeted delivery, and
with the recent approvals of GIVLAARI (givosiran) for the treatment of acute
hepatic porphyria, OXLUMO (lumasiran) for the treatment of primary
hyperoxaluria, and Leqvio (inclisiran) for the treatment of
hypercholesterolemia, the technology has been well validated clinically.
Although much knowledge has been gained over decades of development, there is a
paucity of published literature on the drug metabolism and pharmacokinetic
properties of GalNAc-siRNA. With this in mind, the goals of this minireview are
to provide an aggregate analysis of these nonclinical absorption, distribution,
metabolism, and excretion (ADME) data to build confidence on the translation of
these properties to human. Upon subcutaneous administration, GalNAc-conjugated
siRNAs are quickly distributed to the liver, resulting in plasma pharmacokinetic
(PK) properties that reflect rapid elimination through asialoglycoprotein
receptor-mediated uptake from circulation into hepatocytes. These studies
confirm that liver PK, including half-life and, most importantly, siRNA levels
in RNA-induced silencing complex in hepatocytes, are better predictors of
pharmacodynamics (PD) than plasma PK. Several in vitro and in vivo nonclinical
studies were conducted to characterize the ADME properties of GalNAc-conjugated
siRNAs. These studies demonstrate that the PK/PD and ADME properties of
GalNAc-conjugated siRNAs are highly conserved across species, are largely
predictable, and can be accurately scaled to human, allowing us to identify
efficacious and safe clinical dosing regimens in the absence of human liver PK
profiles. SIGNIFICANCE STATEMENT: Several nonclinical ADME studies have been
conducted in order to provide a comprehensive overview of the disposition and
elimination of GalNAc-conjugated siRNAs and the pharmacokinetic/pharmacodynamic
translation between species. These studies demonstrate that the ADME properties
of GalNAc-conjugated siRNAs are well correlated and predictable across species,
building confidence in the ability to extrapolate to human.
Copyright © 2022 by The Author(s).
DOI: 10.1124/dmd.121.000428
PMID: 34154993 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33985991 | 1. Clin J Am Soc Nephrol. 2021 Jul;16(7):1025-1036. doi: 10.2215/CJN.14730920.
Epub 2021 May 13.
Phase 1/2 Study of Lumasiran for Treatment of Primary Hyperoxaluria Type 1: A
Placebo-Controlled Randomized Clinical Trial.
Frishberg Y(1), Deschênes G(2), Groothoff JW(3), Hulton SA(4), Magen D(5),
Harambat J(6), Van't Hoff WG(7), Lorch U(8), Milliner DS(9), Lieske JC(9),
Haslett P(10), Garg PP(10), Vaishnaw AK(10), Talamudupula S(10), Lu J(10),
Habtemariam BA(10), Erbe DV(10), McGregor TL(10), Cochat P(11)(12); study
collaborators.
Collaborators: Bandara A, Bowen J, Chong WL, Coates S, De Barr P, De Beer J,
Gayed J, Hill T, Kotak A, Ono J, Taubel J, Thayalan M, Wong R, Coch C, Coenen M,
Feldkotter M, Heiland NH, Hohenadel M, Hoppe B, Kyrieleis H, Schalk G, Cooper L,
Gupta A, Milford D, Muorah M, Bacchetta J, Bernoux D, Bertholet-Thomas A,
Cheyssac E, Portefaix A, Ranchin B, Sellier-Leclerc AL, Llanas B, Baudouin V,
Couderc A, Hogan J, Kaguelidou F, Kwon T, Maisin A, Sas D, Becker-Cohen R,
Ben-Shalom E, Rinat C, Behr ST, Bockenhauer D, Mansour B, Pollack S, Garrelfs S,
Oosterveld M, Moochhala S, Walsh S, Kamesh L, Lipkin G.
Author information:
(1)Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem,
Israel.
(2)Department of Pediatric Nephrology, Hôpital Robert Debré, Paris, France.
(3)Department of Pediatric Nephrology, University of Amsterdam, Amsterdam, The
Netherlands.
(4)Department of Nephrology, Birmingham Women's and Children's Hospital,
Birmingham, United Kingdom.
(5)Pediatric Nephrology Institute, Ruth Children's Hospital, Haifa, Israel.
(6)Pediatric Nephrology Unit, Bordeaux University Hospital, Bordeaux, France.
(7)Department of Paediatric Nephrology, Great Ormond Street Hospital, London,
United Kingdom.
(8)Richmond Pharmacology Ltd., London, United Kingdom.
(9)Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota.
(10)Alnylam Pharmaceuticals, Cambridge, Massachusetts.
(11)Center for Rare Renal Diseases and Institut National de la Santé et de la
Recherche Médicale Pediatric Clinical Investigation Center, Hospices Civils de
Lyon, Lyon, France.
(12)Université de Lyon, Lyon, France.
Comment in
Int J Surg. 2023 Feb 01;109(2):83-84. doi: 10.1097/JS9.0000000000000143.
BACKGROUND AND OBJECTIVES: In the rare disease primary hyperoxaluria type 1,
overproduction of oxalate by the liver causes kidney stones, nephrocalcinosis,
kidney failure, and systemic oxalosis. Lumasiran, an RNA interference
therapeutic, suppresses glycolate oxidase, reducing hepatic oxalate production.
The objective of this first-in-human, randomized, placebo-controlled trial was
to evaluate the safety, pharmacokinetic, and pharmacodynamic profiles of
lumasiran in healthy participants and patients with primary hyperoxaluria type
1.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This phase 1/2 study was
conducted in two parts. In part A, healthy adults randomized 3:1 received a
single subcutaneous dose of lumasiran or placebo in ascending dose groups (0.3-6
mg/kg). In part B, patients with primary hyperoxaluria type 1 randomized 3:1
received up to three doses of lumasiran or placebo in cohorts of 1 or 3 mg/kg
monthly or 3 mg/kg quarterly. Patients initially assigned to placebo crossed
over to lumasiran on day 85. The primary outcome was incidence of adverse
events. Secondary outcomes included pharmacokinetic and pharmacodynamic
parameters, including measures of oxalate in patients with primary hyperoxaluria
type 1. Data were analyzed using descriptive statistics.
RESULTS: Thirty-two healthy participants and 20 adult and pediatric patients
with primary hyperoxaluria type 1 were enrolled. Lumasiran had an acceptable
safety profile, with no serious adverse events or study discontinuations
attributed to treatment. In part A, increases in mean plasma glycolate
concentration, a measure of target engagement, were observed in healthy
participants. In part B, patients with primary hyperoxaluria type 1 had a mean
maximal reduction from baseline of 75% across dosing cohorts in 24-hour urinary
oxalate excretion. All patients achieved urinary oxalate levels ≤1.5 times the
upper limit of normal.
CONCLUSIONS: Lumasiran had an acceptable safety profile and reduced urinary
oxalate excretion in all patients with primary hyperoxaluria type 1 to
near-normal levels.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Study of Lumasiran in
Healthy Adults and Patients with Primary Hyperoxaluria Type 1, NCT02706886.
Copyright © 2021 by the American Society of Nephrology.
DOI: 10.2215/CJN.14730920
PMCID: PMC8425611
PMID: 33985991 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33789010 | 1. N Engl J Med. 2021 Apr 1;384(13):1216-1226. doi: 10.1056/NEJMoa2021712.
Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1.
Garrelfs SF(1), Frishberg Y(1), Hulton SA(1), Koren MJ(1), O'Riordan WD(1),
Cochat P(1), Deschênes G(1), Shasha-Lavsky H(1), Saland JM(1), Van't Hoff WG(1),
Fuster DG(1), Magen D(1), Moochhala SH(1), Schalk G(1), Simkova E(1), Groothoff
JW(1), Sas DJ(1), Meliambro KA(1), Lu J(1), Sweetser MT(1), Garg PP(1), Vaishnaw
AK(1), Gansner JM(1), McGregor TL(1), Lieske JC(1); ILLUMINATE-A Collaborators.
Collaborators: Alasrawi S, Arampatzis S, Aung-Din K, Bacchetta J, Bartilucci D,
Baudouin V, Benchimol C, Becker-Cohen R, Ben-Shalom E, Walsh SB, Berdaguer M,
Bockenhauer D, Borema T, Chan L, Chu H, Coch C, Coenen M, Cooper L, Couderc A,
Dossier C, Doye E, Dubourg L, Garvey J, Gupta A, Gupta M, Habeeb S, Hayes W,
Harambat J, Hohenadel M, Hoppe B, Hotchkiss H, Jacqmein J, Kaguelidou F, Kwon T,
Lee K, Lemoine S, Llanas B, Lorenz E, Maisin A, Mansour B, Milliner D, Muorah M,
Oosterveld M, Overcash JS, Prasad P, Portefaix A, Pollack S, Paz Z, Patel A,
Ranchin B, Reid-Adam J, Rinat C, Rothstein M, Schulte I, Sellier-Leclerc AL,
Tran C, Tzvi Behr S, Videen J, Vogt B, Weinbrand-Goichberg J, Weissman I, Zepeda
K, Greenbaum A, Goldfarb D, Schaefer F, Heubi JE, Doros G.
Author information:
(1)From the Department of Pediatric Nephrology, Emma Children's Hospital,
Amsterdam UMC, University of Amsterdam, Amsterdam (S.F.G., J.W.G.); the Division
of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem (Y.F.); the
Department of Nephrology, Birmingham Women's and Children's Hospital, Birmingham
(S.A.H.), and the Department of Paediatric Nephrology, Great Ormond Street
Hospital (W.G.H.), and UCL Department of Renal Medicine, Royal Free Hospital
(S.H.M.), London - both in the United Kingdom; Jacksonville Center for Clinical
Research, Jacksonville, FL (M.J.K.); eStudySite, San Diego, CA (W.D.O.); Center
for Rare Renal Diseases and INSERM Pediatric Clinical Investigation
Center-Hospices Civils de Lyon and Université de Lyon, Lyon (P.C.), and the
Department of Pediatric Nephrology, Hôpital Robert-Debré, Paris (G.D.) - both in
France; the Pediatric Nephrology Unit, Galilee Medical Center, Nahariya
(H.S.-L.), and the Pediatric Nephrology Institute, Rambam Health Care Campus,
Haifa (D.M.) - both in Israel; the Icahn School of Medicine at Mount Sinai, New
York (J.M.S., K.A.M.); the Department of Nephrology and Hypertension,
Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
(D.G.F.); the University of Bonn, Bonn, Germany (G.S.); Al Jalila Children's
Hospital, Dubai, United Arab Emirates (E.S.); the Divisions of Pediatric
Nephrology and Hypertension (D.J.S.) and Nephrology and Hypertension (J.C.L.),
Mayo Clinic, Rochester, MN; and Alnylam Pharmaceuticals, Cambridge, MA (J.L.,
M.T.S., P.P.G., A.K.V., J.M.G., T.L.M.).
Comment in
Kidney Int. 2022 Feb;101(2):208-211. doi: 10.1016/j.kint.2021.05.027.
Nat Rev Nephrol. 2021 Sep;17(9):573-574. doi: 10.1038/s41581-021-00449-9.
N Engl J Med. 2021 Nov 11;385(20):e69. doi: 10.1056/NEJMc2107661.
BACKGROUND: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused
by hepatic overproduction of oxalate that leads to kidney stones,
nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an
investigational RNA interference (RNAi) therapeutic agent, reduces hepatic
oxalate production by targeting glycolate oxidase.
METHODS: In this double-blind, phase 3 trial, we randomly assigned (in a 2:1
ratio) patients with PH1 who were 6 years of age or older to receive
subcutaneous lumasiran or placebo for 6 months (with doses given at baseline and
at months 1, 2, 3, and 6). The primary end point was the percent change in
24-hour urinary oxalate excretion from baseline to month 6 (mean percent change
across months 3 through 6). Secondary end points included the percent change in
the plasma oxalate level from baseline to month 6 (mean percent change across
months 3 through 6) and the percentage of patients with 24-hour urinary oxalate
excretion no higher than 1.5 times the upper limit of the normal range at month
6.
RESULTS: A total of 39 patients underwent randomization; 26 were assigned to the
lumasiran group and 13 to the placebo group. The least-squares mean difference
in the change in 24-hour urinary oxalate excretion (lumasiran minus placebo) was
-53.5 percentage points (P<0.001), with a reduction in the lumasiran group of
65.4% and an effect seen as early as month 1. The between-group differences for
all hierarchically tested secondary end points were significant. The difference
in the percent change in the plasma oxalate level (lumasiran minus placebo) was
-39.5 percentage points (P<0.001). In the lumasiran group, 84% of patients had
24-hour urinary oxalate excretion no higher than 1.5 times the upper limit of
the normal range at month 6, as compared with 0% in the placebo group (P<0.001).
Mild, transient injection-site reactions were reported in 38% of
lumasiran-treated patients.
CONCLUSIONS: Lumasiran reduced urinary oxalate excretion, the cause of
progressive kidney failure in PH1. The majority of patients who received
lumasiran had normal or near-normal levels after 6 months of treatment. (Funded
by Alnylam Pharmaceuticals; ILLUMINATE-A ClinicalTrials.gov number,
NCT03681184.).
Copyright © 2021 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2021712
PMID: 33789010 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35015123 | 1. Pediatr Nephrol. 2022 Apr;37(4):907-911. doi: 10.1007/s00467-021-05393-1. Epub
2022 Jan 11.
The effect of lumasiran therapy for primary hyperoxaluria type 1 in small
infants.
Méaux MN(1)(2)(3), Sellier-Leclerc AL(1), Acquaviva-Bourdain C(4), Harambat
J(2), Allard L(2), Bacchetta J(5)(6)(7).
Author information:
(1)Service de Néphrologie Rhumatologie Et Dermatologie Pédiatriques, Centre de
Référence Des Maladies Rénales Rares Néphrogones Filières Maladies Rares ORKID
et ERK-Net, Hospices Civils de Lyon, Lyon, Bron, France.
(2)Service de Néphrologie Pédiatrique, Centre de Référence Des Maladies Rénales
Rares Sorare, Filière Maladie Rare ORKID, CHU de Bordeaux, Bordeaux, France.
(3)Service Biochimie Et Biologie Moléculaire, Maladies Héréditaires du
Métabolisme, Hospices Civils de Lyon, Bron, France.
(4)INSERM, UMR 1033, Faculté de Médecine Lyon Est, Université Claude Bernard
Lyon1, Lyon, France.
(5)Service de Néphrologie Rhumatologie Et Dermatologie Pédiatriques, Centre de
Référence Des Maladies Rénales Rares Néphrogones Filières Maladies Rares ORKID
et ERK-Net, Hospices Civils de Lyon, Lyon, Bron, France.
justine.bacchetta@chu-lyon.fr.
(6)Service Biochimie Et Biologie Moléculaire, Maladies Héréditaires du
Métabolisme, Hospices Civils de Lyon, Bron, France.
justine.bacchetta@chu-lyon.fr.
(7)Faculté de Médecine Lyon Est, Université Claude Bernard, Lyon 1, Lyon,
France. justine.bacchetta@chu-lyon.fr.
Comment in
J Nephrol. 2023 Mar;36(2):323-327. doi: 10.1007/s40620-022-01443-5.
BACKGROUND: Lumasiran, a sub-cutaneous RNA-interference therapy, has been
recently approved for primary hyperoxaluria type 1 (PH1), with doses and
intervals according to body weight. Little is known as to its use in infants;
the aim of this study was to describe treatment outcome in 3 infants who
received lumasiran therapy before 2 years of age.
CASE-DIAGNOSIS/TREATMENT: Patient 1 was diagnosed antenatally and received
lumasiran from day 9. According to the product information template (PIT), he
received monthly lumasiran (3 times at 6 mg/kg, then 3 mg/kg), with
hyperhydration and potassium citrate. Despite decreased plasma oxalate levels,
persistent normal kidney function, and good tolerance, kidney ultrasound
performed after 2 months found nephrocalcinosis, without normalization of
urinary oxalate (UOx). The dose was increased back to 6 mg/kg, inducing a
normalization in UOx. Nephrocalcinosis started to improve at month 10. Patient 2
was diagnosed at 2.5 months (acute kidney failure); nephrocalcinosis was present
from diagnosis. She received monthly lumasiran (6 mg/kg), with progressive
decrease in UOx and substantial improvement in kidney function but stable
nephrocalcinosis after 9 injections. Patient 3 was diagnosed fortuitously
(nephrocalcinosis) at 3.5 months and received lumasiran before genetic
diagnosis, leading to decreased UOx and maintenance of normal kidney function.
Nephrocalcinosis improved after 5 injections.
CONCLUSIONS: This report presents the youngest children treated with lumasiran
worldwide. Lumasiran seems effective without side effects in infants but does
not completely prevent the onset of nephrocalcinosis in the most severe forms.
Higher doses than those proposed in the PIT might be required because of hepatic
immaturity.
© 2022. The Author(s), under exclusive licence to International Pediatric
Nephrology Association.
DOI: 10.1007/s00467-021-05393-1
PMID: 35015123 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35731461 | 1. BioDrugs. 2022 Jul;36(4):437-441. doi: 10.1007/s40259-022-00539-5. Epub 2022
Jun 22.
Progress with RNA Interference for the Treatment of Primary Hyperoxaluria.
Sawyer K(1), Leahy S(1), Wood KD(2).
Author information:
(1)Marnix E. Heersink School of Medicine, University of Alabama at Birmingham,
Birmingham, AL, USA.
(2)Department of Urology, University of Alabama at Birmingham, 1720 2nd Ave
South, Birmingham, AL, 35294, USA. kylewood@uabmc.edu.
Over the last few years, US Food and Drug Administration-approved drugs using
RNA interference have come to the market. Many have treated liver-specific
diseases utilizing N-acetyl galactosamine conjugation because of its effective
delivery and limited off-target effects. The autosomal recessive disorder
primary hyperoxaluria, specifically type 1, has benefited from these
developments. Primary hyperoxaluria arises from mutations in the enzymes
involved in endogenous oxalate synthesis. The severity of disease varies but can
result in kidney failure and systemic oxalosis. Until recently, the treatment
options were limited and focused primarily on supportive treatments, pyridoxine
use in a subset of patients with primary hyperoxaluria type 1, and liver-kidney
transplants in those who progressed to kidney failure. Two genes have been
targeted with RNA interference; lumasiran targets glycolate oxidase and
nedosiran targets lactate dehydrogenase A. Lumasiran was recently approved in
the treatment of primary hyperoxaluria type 1 and nedosiran is in the approval
process. Unfortunately, despite initial hopes that nedosiran may also be a
treatment option for primary hyperoxaluria types 2 and 3, initial data suggest
otherwise. The use of RNA interference liver-specific targeting for the
treatment of primary hyperoxaluria type 1 will likely transform the natural
history of the disease.
© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland
AG.
DOI: 10.1007/s40259-022-00539-5
PMID: 35731461 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35237473 | 1. Cureus. 2022 Jan 27;14(1):e21673. doi: 10.7759/cureus.21673. eCollection 2022
Jan.
Infantile Primary Hyperoxaluria Type 1 Treated With Lumasiran in Twin Males.
Aldabek K(1), Grossman OK(2), Al-Omar O(1), Fox JA(3), Moritz ML(4)(5).
Author information:
(1)Urology/Pediatric Urology, WVU Medicine Children's Hospital/West Virginia
University School of Medicine, Morgantown, USA.
(2)Pediatrics/Pediatric Nephrology, WVU Medicine Children's Hospital/West
Virginia University School of Medicine, Morgantown, USA.
(3)Urology/Pediatric Urology, UPMC Children's Hospital of Pittsburgh/University
of Pittsburgh School of Medicine, Pittsburgh, USA.
(4)Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, USA.
(5)Pediatric Nephrology, UPMC Children's Hospital of Pittsburgh, Pittsburgh,
USA.
Primary hyperoxaluria type 1 (PH1) is a rare genetic disease that results in
oxalate overproduction leading to nephrolithiasis (NL), nephrocalcinosis (NC),
kidney failure, and systemic oxalosis. Infantile PH1 is its most severe form,
and it may require intensive hemodialysis followed by a liver-kidney transplant.
Lumasiran is an RNA interference (RNAi) therapeutic agent that reduces hepatic
oxalate production, which has been recently approved for the treatment of PH1.
In this report, we present a case of twin males with infantile PH1 and bilateral
NL and NC who were treated with lumasiran at 12 months of age. Their symptoms
abated after therapy was started without disease progression. To the best of our
knowledge, this is the first report of PH1 occurring in twins and the first
report on using lumasiran to treat infantile PH1 outside of a clinical trial.
Lumasiran appears to be a successful therapeutic option for infantile PH1.
Copyright © 2022, Aldabek et al.
DOI: 10.7759/cureus.21673
PMCID: PMC8882078
PMID: 35237473
Conflict of interest statement: The authors have declared financial
relationships, which are detailed in the next section. |
http://www.ncbi.nlm.nih.gov/pubmed/34906487 | 1. Genet Med. 2022 Mar;24(3):654-662. doi: 10.1016/j.gim.2021.10.024. Epub 2021
Dec 8.
Phase 3 trial of lumasiran for primary hyperoxaluria type 1: A new RNAi
therapeutic in infants and young children.
Sas DJ(1), Magen D(2), Hayes W(3), Shasha-Lavsky H(4), Michael M(5), Schulte
I(6), Sellier-Leclerc AL(7), Lu J(8), Seddighzadeh A(8), Habtemariam B(8),
McGregor TL(8), Fujita KP(8), Frishberg Y(9); ILLUMINATE-B Workgroup.
Collaborators: Bacchetta J, Baudouin V, Becker-Cohen R, Tzvi Behr S, Ben-Shalom
E, Berdaguer M, Bockenhauer D, Cochat P, Coenen M, Cramer CH, Deschênes G,
Dossier C, Doye E, Feldman LF, Hohenadel M, Kaguelidou F, Zebegret IL, Lieske
JC, Maisin A, Milliner DS, Plonsky Toder M, Pollack S, Portefaix A, Ranchin B,
Rinat C, Safdar A, Schalk G, Srivaths PR, Tran CL, Van't Hoff W,
Weinbrand-Goichberg J, Weissman I.
Author information:
(1)Division of Pediatric Nephrology and Hypertension, Mayo Clinic, Rochester,
MN. Electronic address: sas.david@mayo.edu.
(2)Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa, Israel.
(3)Department of Paediatric Nephrology, Great Ormond Street Hospital, London,
United Kingdom.
(4)Pediatric Nephrology Unit, Galilee Medical Center, Nahariya, Israel.
(5)Division of Pediatric Nephrology, Department of Pediatrics, Texas Children's
Hospital/Baylor College of Medicine, Houston, TX.
(6)Department of Pediatric Nephrology, University of Bonn, Bonn, Germany.
(7)Hôpital Femme Mère Enfant and Centre d'Investigation Clinique Inserm,
Hospices Civils de Lyon, ERKnet, Bron, France.
(8)Alnylam Pharmaceuticals, Cambridge, MA.
(9)Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem,
Israel; Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
Electronic address: Yaacovf@ekmd.huji.ac.il.
PURPOSE: Primary hyperoxaluria type 1 (PH1) is a rare, progressive, genetic
disease with limited treatment options. We report the efficacy and safety of
lumasiran, an RNA interference therapeutic, in infants and young children with
PH1.
METHODS: This single-arm, open-label, phase 3 study evaluated lumasiran in
patients aged <6 years with PH1 and an estimated glomerular filtration rate >45
mL/min/1.73 m2, if aged ≥12 months, or normal serum creatinine, if aged <12
months. The primary end point was percent change in spot urinary oxalate to
creatinine ratio (UOx:Cr) from baseline to month 6. Secondary end points
included proportion of patients with urinary oxalate ≤1.5× upper limit of normal
and change in plasma oxalate.
RESULTS: All patients (N = 18) completed the 6-month primary analysis period.
Median age at consent was 50.1 months. Least-squares mean percent reduction in
spot UOx:Cr was 72.0%. At month 6, 50% of patients (9/18) achieved spot UOx:Cr
≤1.5× upper limit of normal. Least-squares mean percent reduction in plasma
oxalate was 31.7%. The most common treatment-related adverse events were
transient, mild, injection-site reactions.
CONCLUSION: Lumasiran showed rapid, sustained reduction in spot UOx:Cr and
plasma oxalate and acceptable safety in patients aged <6 years with PH1,
establishing RNA interference therapies as safe, effective treatment options for
infants and young children.
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.gim.2021.10.024
PMID: 34906487 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of Interest David J. Sas reports grants
and other support from Alnylam Pharmaceuticals and personal fees from Advicenne.
Daniella Magen reports research funding, consultancy fees, and nonfinancial
support from Alnylam Pharmaceuticals. Wesley Hayes reports travel and
accommodation expenses from Alnylam Pharmaceuticals to attend an international
investigators’ meeting. Hadas Shasha-Lavsky reports serving as a principal
investigator for Alnylam Pharmaceuticals and receiving travel and accommodation
expenses from Alnylam Pharmaceuticals to attend international investigators’
meetings. Mini Michael reports serving as a principal investigator for and
receiving travel and accommodation expenses from Alnylam Pharmaceuticals to
attend international investigators’ meetings. Anne-Laure Sellier-Leclerc reports
consultancy fees from Alnylam Pharmaceuticals and Dicerna Pharmaceuticals and
was principal investigator for research funded by OxThera. Ali Seddighzadeh
reports previous employment by and shareholder of Alnylam Pharmaceuticals
(currently employed by Apellis Pharmaceuticals). Jiandong Lu, Bahru Habtemariam,
Tracy L. McGregor, and Kenji P. Fujita report previous employment by and
shareholder of Alnylam Pharmaceuticals. Yaacov Frishberg reports consultancy
fees from Alnylam Pharmaceuticals and membership in the safety review committee.
All other authors declare no conflicts of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/34022071 | 1. Br J Clin Pharmacol. 2022 Jun;88(6):2525-2538. doi: 10.1111/bcp.14925. Epub
2021 Jun 11.
Therapeutic RNA interference: A novel approach to the treatment of primary
hyperoxaluria.
Forbes TA(1)(2)(3), Brown BD(4), Lai C(4).
Author information:
(1)Royal Children's Hospital, Parkville, Victoria, Australia.
(2)Murdoch Children's Research Institute, Parkville, Victoria, Australia.
(3)University of Melbourne, Parkville, Victoria, Australia.
(4)Dicerna Pharmaceuticals, Cambridge, MA, USA.
RNA interference (RNAi) is a natural biological pathway that inhibits gene
expression by targeted degradation or translational inhibition of cytoplasmic
mRNA by the RNA induced silencing complex. RNAi has long been exploited in
laboratory research to study the biological consequences of the reduced
expression of a gene of interest. More recently RNAi has been demonstrated as a
therapeutic avenue for rare metabolic diseases. This review presents an overview
of the cellular RNAi machinery as well as therapeutic RNAi design and delivery.
As a clinical example we present primary hyperoxaluria, an ultrarare inherited
disease of increased hepatic oxalate production which leads to recurrent calcium
oxalate kidney stones. In the most common form of the disease (Type 1),
end-stage kidney disease occurs in childhood or young adulthood, often
necessitating combined kidney and liver transplantation. In this context we
discuss nedosiran (Dicerna Pharmaceuticals, Inc.) and lumasiran (Alnylam
Pharmaceuticals), which are both novel RNAi therapies for primary hyperoxaluria
that selectively reduce hepatic expression of lactate dehydrogenase and
glycolate oxidase respectively, reducing hepatic oxalate production and urinary
oxalate levels. Finally, we consider future optimizations advances in RNAi
therapies.
© 2021 The Authors. British Journal of Clinical Pharmacology published by John
Wiley & Sons Ltd on behalf of British Pharmacological Society.
DOI: 10.1111/bcp.14925
PMCID: PMC9291495
PMID: 34022071 [Indexed for MEDLINE]
Conflict of interest statement: C.L. and B.D.B. are employees of Dicerna
Pharmaceuticals, which is developing siRNAs as therapeutics, including
nedosiran. T.A.F. is the Site Principle Investigator at the Royal Children's
Hospital in Melbourne, Australia supervising Dicerna (nedosiran) and Alnylam
(lumasiran) clinical trials. |
http://www.ncbi.nlm.nih.gov/pubmed/35843439 | 1. Am J Kidney Dis. 2023 Feb;81(2):145-155.e1. doi: 10.1053/j.ajkd.2022.05.012.
Epub 2022 Jul 14.
Lumasiran for Advanced Primary Hyperoxaluria Type 1: Phase 3 ILLUMINATE-C Trial.
Michael M(1), Groothoff JW(2), Shasha-Lavsky H(3), Lieske JC(4), Frishberg Y(5),
Simkova E(6), Sellier-Leclerc AL(7), Devresse A(8), Guebre-Egziabher F(9),
Bakkaloglu SA(10), Mourani C(11), Saqan R(12), Singer R(13), Willey R(14),
Habtemariam B(14), Gansner JM(14), Bhan I(14), McGregor T(14), Magen D(15).
Author information:
(1)Division of Pediatric Nephrology, Department of Pediatrics, Texas Children's
Hospital/Baylor College of Medicine, Houston, Texas. Electronic address:
mmichael@bcm.edu.
(2)Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC,
University of Amsterdam, Amsterdam, The Netherlands.
(3)Pediatric Nephrology Unit, Galilee Medical Center, Azrieli Faculty of
Medicine, Bar Ilan University, Nahariya, Israel.
(4)Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota.
(5)Division of Pediatric Nephrology, Shaare Zedek Medical Center, Faculty of
Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
(6)Nephrology - Medical Affairs, Al Jalila Children's Hospital, Dubai, United
Arab Emirates.
(7)Hôpital Femme Mère Enfant en Centre d'Investigation Clinique, Institut
National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de
Lyon, ERKnet, Bron, France.
(8)Division of Nephrology, Cliniques Universitaires Saint-Luc, Brussels,
Belgium.
(9)Nephrology and Renal Function Unit, Edouard Herriot Hospital, Hospices Civils
de Lyon, INSERM 1060, Lyon, France.
(10)Department of Pediatric Nephrology, Faculty of Medicine, Gazi University,
Ankara, Turkey.
(11)Department of Pediatrics, Hôtel-Dieu de France Hospital, Beirut, Lebanon.
(12)Pharmaceutical Research Center, Jordan University of Science and Technology,
Irbid, Jordan.
(13)Renal Service, Canberra Health Services, Garran, ACT, Australia.
(14)Alnylam Pharmaceuticals, Cambridge, Massachusetts.
(15)Pediatric Nephrology Institute, Rambam Health Care Campus, Haifa, Israel.
Comment in
J Urol. 2023 Aug;210(2):375-377. doi: 10.1097/JU.0000000000003538.
RATIONALE & OBJECTIVE: Lumasiran reduces urinary and plasma oxalate (POx) in
patients with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney
function. ILLUMINATE-C evaluates the efficacy, safety, pharmacokinetics, and
pharmacodynamics of lumasiran in patients with PH1 and advanced kidney disease.
STUDY DESIGN: Phase 3, open-label, single-arm trial.
SETTING & PARTICIPANTS: Multinational study; enrolled patients with PH1 of all
ages, estimated glomerular filtration rate ≤45 mL/min/1.73 m2 (if age ≥12
months) or increased serum creatinine level (if age <12 months), and POx ≥20
μmol/L at screening, including patients with or without systemic oxalosis.
INTERVENTION: Lumasiran administered subcutaneously; 3 monthly doses followed by
monthly or quarterly weight-based dosing.
OUTCOME: Primary end point: percent change in POx from baseline to month 6
(cohort A; not receiving hemodialysis at enrollment) and percent change in
predialysis POx from baseline to month 6 (cohort B; receiving hemodialysis at
enrollment). Pharmacodynamic secondary end points: percent change in POx area
under the curve between dialysis sessions (cohort B only); absolute change in
POx; percent and absolute change in spot urinary oxalate-creatinine ratio; and
24-hour urinary oxalate adjusted for body surface area.
RESULTS: All patients (N = 21; 43% female; 76% White) completed the 6-month
primary analysis period. Median age at consent was 8 (range, 0-59) years. For
the primary end point, least-squares mean reductions in POx were 33.3% (95%
CI, -15.2% to 81.8%) in cohort A (n = 6) and 42.4% (95% CI, 34.2%-50.7%) in
cohort B (n = 15). Improvements were also observed in all pharmacodynamic
secondary end points. Most adverse events were mild or moderate. No patient
discontinued treatment or withdrew from the study. The most commonly reported
lumasiran-related adverse events were injection-site reactions, all of which
were mild and transient.
LIMITATIONS: Single-arm study without placebo control.
CONCLUSIONS: Lumasiran resulted in substantial reductions in POx with acceptable
safety in patients with PH1 who have advanced kidney disease, supporting its
efficacy and safety in this patient population.
FUNDING: Alnylam Pharmaceuticals.
TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number
NCT04152200 and at EudraCT with study number 2019-001346-17.
PLAIN-LANGUAGE SUMMARY: Primary hyperoxaluria type 1 (PH1) is a rare genetic
disease characterized by excessive hepatic oxalate production that frequently
causes kidney failure. Lumasiran is an RNA interference therapeutic that is
administered subcutaneously for the treatment of PH1. Lumasiran has been shown
to reduce oxalate levels in the urine and plasma of patients with PH1 who have
relatively preserved kidney function. In the ILLUMINATE-C study, the efficacy
and safety of lumasiran were evaluated in patients with PH1 and advanced kidney
disease, including a cohort of patients undergoing hemodialysis. During the
6-month primary analysis period, lumasiran resulted in substantial reductions in
plasma oxalate with acceptable safety in patients with PH1 complicated by
advanced kidney disease.
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
DOI: 10.1053/j.ajkd.2022.05.012
PMID: 35843439 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35747094 | 1. Int J Nephrol Renovasc Dis. 2022 Jun 17;15:197-206. doi:
10.2147/IJNRD.S293682. eCollection 2022.
Lumasiran in the Management of Patients with Primary Hyperoxaluria Type 1: From
Bench to Bedside.
D'Ambrosio V(1)(2), Ferraro PM(1)(2).
Author information:
(1)U.O.S. Terapia Conservativa della Malattia Renale Cronica, U.O.C. Nefrologia,
Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico
Universitario A. Gemelli IRCCS, Roma, Italia.
(2)Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università
Cattolica del Sacro Cuore, Roma, Italia.
Primary hyperoxaluria (PH) is a rare genetic disease caused by excessive hepatic
production and elevated urinary excretion of oxalate that leads to recurrent
nephrolithiasis, nephrocalcinosis and, eventually, kidney failure. As glomerular
filtration rate declines, oxalate accumulates leading to systemic oxalosis, a
debilitating condition with high morbidity and mortality. Although PH is usually
diagnosed during infancy, it can present at any age with different phenotypes,
ranging from mild symptoms to extremely debilitating manifestations. PH is an
autosomal recessive disorder and, to date, three types have been identified:
PH1, PH2 and PH3. PH1 is the most common and most aggressive type, accounting
for almost 80% of primary hyperoxaluria diagnoses. Until 2020, general treatment
for PH1 consisted mainly in high fluid intake, urine alkalization, surgical
management of recurrent nephrolithiasis and eventually, if and when kidney
failure occurred, intensive dialysis regimens and transplantation strategies
(simultaneous or sequential liver-kidney transplant or isolated liver/kidney
transplant in carefully selected patients). Specific treatment did and still
consists in administration of pyridoxine hydrochloride, although it is only
effective in a subset of PH1 patients. Lumasiran, a novel biological drug based
on mRNA interference that has been recently approved in the US and European
Union, showed promising results and is set to be a turning point in the
management of PH1. This literature review aims to summarize the available
evidence on PH1 treatment with lumasiran, in order to provide both pediatric and
adult nephrologists and clinicians with the knowledge for the identification and
management of PH1 patients suitable for treatment.
© 2022 D’Ambrosio and Ferraro.
DOI: 10.2147/IJNRD.S293682
PMCID: PMC9211742
PMID: 35747094
Conflict of interest statement: PMF received consultant fees and grant support
from Allena Pharmaceuticals, Alnylam, AstraZeneca, BioHealth Italia, Otsuka
Pharmaceuticals, Vifor Fresenius, and royalties as an author for UpToDate. VDA
received consultant fees from Allena Pharmaceuticals. PMF and VDA are members of
the European Reference Network for Rare Kidney Diseases (ERKNet) – Project ID No
739532. |
http://www.ncbi.nlm.nih.gov/pubmed/33513899 | 1. J Pers Med. 2021 Jan 27;11(2):74. doi: 10.3390/jpm11020074.
Small Molecule-Based Enzyme Inhibitors in the Treatment of Primary
Hyperoxalurias.
Moya-Garzon MD(1)(2)(3), Gomez-Vidal JA(1), Alejo-Armijo A(4), Altarejos J(4),
Rodriguez-Madoz JR(5)(6), Fernandes MX(7), Salido E(8), Salido S(4),
Diaz-Gavilan M(1).
Author information:
(1)Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Campus
de Cartuja s/n, 18071 Granada, Spain.
(2)Department of Pathology, Stanford University School of Medicine, Stanford, CA
94305, USA.
(3)Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA.
(4)Departamento de Química Inorgánica y Orgánica, Facultad de Ciencias
Experimentales, Campus de Excelencia Internacional Agroalimentario (ceiA3),
Universidad de Jaén, 23071 Jaén, Spain.
(5)Programa de Medicina Regenerativa, CIMA Universidad de Navarra, 31008
Pamplona, Spain.
(6)Instituto de Investigación Sanitaria de Navarra, IdiSNA, 31008 Pamplona,
Spain.
(7)Instituto Universitario de Bio-Orgánica "Antonio González", Instituto de
Tecnologías Biomédicas, Universidad de La Laguna, 38206 La Laguna, Spain.
(8)Hospital Universitario de Canarias & Center for Rare Diseases (CIBERER),
38320 Tenerife, Spain.
Primary hyperoxalurias (PHs) are a group of inherited alterations of the hepatic
glyoxylate metabolism. PHs classification based on gene mutations parallel a
variety of enzymatic defects, and all involve the harmful accumulation of
calcium oxalate crystals that produce systemic damage. These geographically
widespread rare diseases have a deep impact in the life quality of the patients.
Until recently, treatments were limited to palliative measures and kidney/liver
transplants in the most severe forms. Efforts made to develop pharmacological
treatments succeeded with the biotechnological agent lumasiran, a siRNA product
against glycolate oxidase, which has become the first effective therapy to treat
PH1. However, small molecule drugs have classically been preferred since they
benefit from experience and have better pharmacological properties. The
development of small molecule inhibitors designed against key enzymes of
glyoxylate metabolism is on the focus of research. Enzyme inhibitors are
successful and widely used in several diseases and their pharmacokinetic
advantages are well known. In PHs, effective enzymatic targets have been
determined and characterized for drug design and interesting inhibitory
activities have been achieved both in vitro and in vivo. This review describes
the most recent advances towards the development of small molecule enzyme
inhibitors in the treatment of PHs, introducing the multi-target approach as a
more effective and safe therapeutic option.
DOI: 10.3390/jpm11020074
PMCID: PMC7912158
PMID: 33513899
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/33497125 | 1. Am J Nurs. 2021 Feb 1;121(2):27. doi: 10.1097/01.NAJ.0000734120.60377.79.
New Drugs for Rare Disorders.
Aschenbrenner DS(1).
Author information:
(1)Diane S. Aschenbrenner is an assistant professor at Notre Dame of Maryland
University in Baltimore. She also coordinates Drug Watch :
daschenbrenner@ndm.edu .
Several new drugs have been approved to treat rare genetic disorders:
setmelanotide for certain conditions causing obesity; lumasiran for primary
hyperoxaluria type 1, a kidney disorder; and lonafarnib for two diseases that
cause premature aging.
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/01.NAJ.0000734120.60377.79
PMID: 33497125 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33297799 | 1. J Asthma. 2022 Feb;59(2):239-242. doi: 10.1080/02770903.2020.1861622. Epub
2020 Dec 16.
Severe asthma and COVID-19: lessons from the first wave.
Patrucco F(1)(2), Benfante A(3), Villa E(4), Principe S(3), Scichilone N(3),
Solidoro P(5)(6).
Author information:
(1)Medical and Specialistic Department, Division of Respiratory Diseases, AOU
Maggiore della Carità, Novara, Italy.
(2)Translational Medicine Department, University of Piemonte Orientale, Novara,
Italy.
(3)PROMISE Department, University of Palermo, Palermo, Italy.
(4)Pneumology Unit, ASL Genova 3, Villa Scassi Hospital, Genova, Italy.
(5)Medical Sciences Department, University of Turin, Torino, Italy.
(6)Cardiovascular and Thoracic Department, Pneumology Unit U, AOU Città della
Salute e della Scienza di Torino, University of Turin, Torino, Italy.
OBJECTIVE: Severe asthma is considered a risk factor for SARS-Coronavirus 2
(SARS-CoV-2) infection but scientific evidences are lacking.
METHODS: we performed a literature search and review based on PubMed database
national, international recommendations as well as papers on severe asthmatic
patients and their management during SARS-CoV-2 pandemic.
RESULTS: the majority of international recommendations, expert panels and
editorials provide indications about management of severe asthmatic patients. No
published studies evaluated the effects of biologic agents on severe asthmatic
patients during SARS-CoV-2 pandemic.
CONCLUSIONS: the relationship between SARS-CoV-2 and asthma is variable
worldwide and severe asthmatic patients were seldom reported in published
cohorts. International recommendations suggest maintaining asthma under control
to limit exacerbations occurrence, by using all available treatment. The minimum
steroid dosage effective to control symptoms should be maintained to avoid
exacerbations; biologic agents administration should be regularly scheduled
encouraging patient support programmes.
DOI: 10.1080/02770903.2020.1861622
PMID: 33297799 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35887681 | 1. J Pers Med. 2022 Jul 20;12(7):1184. doi: 10.3390/jpm12071184.
COPD, but Not Asthma, Is Associated with Worse Outcomes in COVID-19: Real-Life
Data from Four Main Centers in Northwest Italy.
Nicola S(1)(2), Borrelli R(2), Ridolfi I(2), Bernardi V(2), Borrelli P(3), Guida
G(4), Antonelli A(5), Albera C(6), Marengo S(7), Briozzo A(7), Norbiato C(7),
Frazzetto AV(2), Saad M(6), Lo Sardo L(1)(2), Bacco B(2), Gallo Cassarino S(2),
Della Mura S(2), Bagnasco D(8), Bucca C(2), Rolla G(2), Solidoro P(6), Brussino
L(1)(2).
Author information:
(1)SCDU Immunologia e Allergologia, AO Ordine Mauriziano di Torino, C.so Re
Umberto 109, 10128 Torino, Italy.
(2)Department of Medical Sciences, University of Torino, C.so Dogliotti, 14,
10126 Torino, Italy.
(3)SSD Dermatologia e Allergologia, Ospedale Beauregard, Via Vaccari, 5, 11100
Aosta, Italy.
(4)Dipartimento di Scienze Cliniche e Biologiche, University o Torino, Regione
Gonzole, 10, 10043 Orbassano, Italy.
(5)SS Allergologia e Fisiopatologia Respiratoria, ASO Santa Croce e Carle, Via
Michele Coppino, 26, 12100 Cuneo, Italy.
(6)S.C. Pneumologia U, Azienda Ospedaliero-Universitaria Città della Salute e
della Scienza, Corso Bramante, 88, 10126 Torino, Italy.
(7)SC Medicina Interna, AO Ordine Mauriziano di Torino, Largo Turati 62, 10128
Torino, Italy.
(8)Allergy and Respiratory Diseases, IRCCS Policlinico San Martino, University
of Genoa, 16132 Genoa, Italy.
Introduction: Asthma, along with inhaled steroids, was initially considered a
risk factor for worse clinical outcomes in COVID-19. This was related to the
higher morbidity observed in asthma patients during previous viral outbreaks.
This retrospective study aimed at evaluating the prevalence of asthma among
patients admitted due to SARS-CoV-2 infection as well as the impact of inhaled
therapies on their outcomes. Furthermore, a comparison between patients with
asthma, COPD and the general population was made. Methods: All COVID-19
inpatients were recruited between February and July 2020 from four large
hospitals in Northwest Italy. Data concerning medical history, the Charlson
Comorbidity Index (CCI) and the hospital stay, including length, drugs and
COVID-19 complications (respiratory failure, lung involvement, and the need for
respiratory support) were collected, as well as the type of discharge. Results:
patients with asthma required high-flow oxygen therapy (33.3 vs. 14.3%, p =
0.001) and invasive mechanical ventilation (17.9 vs. 9.5%, p = 0.048) more
frequently when compared to the general population, but no other difference was
observed. Moreover, asthma patients were generally younger than patients with
COPD (59.2 vs. 76.8 years, p < 0.001), they showed both a lower mortality rate
(15.4 vs. 39.4%, p < 0.001) and a lower CCI (3.4 vs. 6.2, p < 0.001). Patients
with asthma in regular therapy with ICS at home had significantly shorter
hospital stay compared to those with no treatments (25.2 vs. 11.3 days, p =
0.024). Discussion: Our study showed that asthma is not associated with worse
outcomes of COVID-19, despite the higher need for respiratory support compared
with the general population, while the use of ICS allowed for a shorter hospital
stay. In addition, the comparison of asthma with COPD patients confirmed the
greater frailty of the latter, according to their multiple comorbidities.
DOI: 10.3390/jpm12071184
PMCID: PMC9321539
PMID: 35887681
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/33461348 | 1. J Asthma. 2022 Apr;59(4):787-790. doi: 10.1080/02770903.2021.1878531. Epub
2021 Feb 8.
Preadmission use of inhaled corticosteroids and risk of fatal or severe
COVID-19: a meta-analysis.
Kow CS(1), Hasan SS(2)(3).
Author information:
(1)School of Postgraduate Studies, International Medical University, Kuala
Lumpur, Malaysia.
(2)Department of Pharmacy, University of Huddersfield, Huddersfield, UK.
(3)School of Biomedical Sciences & Pharmacy, University of Newcastle, Callaghan,
Australia.
Comment on
J Asthma. 2021 Nov;58(11):1536-1543. doi: 10.1080/02770903.2020.1804578.
Objective: With emerging of observational evidence, we aimed to perform a
meta-analysis to summarize the overall effect of the chronic use of inhaled
corticosteroids on the clinical outcomes in patients with coronavirus disease
2019 (COVID-19). Methods:Systematic literature search in electronic databases
was performed to identify observational studies that investigated the
preadmission use of inhaled corticosteroids on the risk of a fatal or severe
course of illness in patients with COVID-19 and reported adjusted measures of
association. Adjusted odds ratios or relative risks and the corresponding 95%
confidence intervals from each study were pooled to produce pooled odds ratio
and 95% confidence interval. Results: The meta-analysis revealed no significant
difference in the risk for the development of a fatal course of COVID-19 with
preadmission use of inhaled corticosteroids in patients with COVID-19 relative
to non-use of inhaled corticosteroids (pooled odds ratio=1.28; 95% confidence
interval 0.73-2.26). Similarly, the meta-analysis observed no significant
difference in the risk for the development of a severe course of COVID-19 with
preadmission use of inhaled corticosteroids in patients with COVID-19 relative
to non-use of inhaled corticosteroids (pooled odds ratio=1.45; 95% confidence
interval 0.96-2.20).Conclusions: Our findings assured the safety of continued
use of inhaled corticosteroids during the COVID-19 pandemic.
DOI: 10.1080/02770903.2021.1878531
PMID: 33461348 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33276252 | 1. Respir Med. 2021 Jan;176:106275. doi: 10.1016/j.rmed.2020.106275. Epub 2020
Nov 28.
Association of inhaled and systemic corticosteroid use with Coronavirus Disease
2019 (COVID-19) test positivity in patients with chronic pulmonary diseases.
Liao SY(1), Petrache I(2), Fingerlin TE(3), Maier LA(4).
Author information:
(1)Department of Medicine, National Jewish Health, Denver, CO, United States;
Department of Medicine, University of Colorado Denver - Anschutz Medical Campus,
Aurora, CO, United States; Colorado School of Public Health, University of
Colorado Denver - Anschutz Medical Campus, Aurora, CO, United States. Electronic
address: liaos@NJHealth.org.
(2)Department of Medicine, National Jewish Health, Denver, CO, United States;
Department of Medicine, University of Colorado Denver - Anschutz Medical Campus,
Aurora, CO, United States.
(3)Colorado School of Public Health, University of Colorado Denver - Anschutz
Medical Campus, Aurora, CO, United States; Department of Biomedical Research,
National Jewish Health, Denver, CO, United States.
(4)Department of Medicine, National Jewish Health, Denver, CO, United States;
Department of Medicine, University of Colorado Denver - Anschutz Medical Campus,
Aurora, CO, United States; Colorado School of Public Health, University of
Colorado Denver - Anschutz Medical Campus, Aurora, CO, United States.
BACKGROUND: The effects of chronic inhaled and systemic corticosteroids use on
COVID-19 susceptibility and severity are unclear. Since many patients with
chronic pulmonary diseases rely on corticosteroids to control disease, it is
important to understand the risks of their use during the pandemic. We aim to
study if the use of inhaled or systemic corticosteroids affects the likelihood
of developing COVID-19 infection.
METHODS: We used the National Jewish Health electronic medical record research
database to identify a cohort of all subjects who were tested for suspected
COVID-19 between March 11 - June 23, 2020. Testing results, medication use, and
comorbidities were obtained from the medical record. Following a comparison of
different propensity score weighting methods, overlap propensity score weighting
was used to analyze the association between medication use and COVID-19
diagnosis.
RESULTS: The cohort consisted of 928 patients, of which 12% tested positive. The
majority (66%) of patients had a history of chronic pulmonary diseases. There
was no significant association between inhaled corticosteroid use and testing
positive for COVID-19. Interestingly, systemic corticosteroid use was associated
with a lower odds ratio (0.95, 95% CI: 0.91-0.99) of testing positive for
COVID-19. Similar results were noted when the analysis was restricted to those
with any chronic pulmonary diseases, with asthma or with chronic obstructive
pulmonary disease (COPD).
CONCLUSIONS: Our study supports the recommendation that patients with chronic
pulmonary diseases, including asthma and COPD who require treatment with either
inhaled or systemic corticosteroids, should continue their use during the
COVID-19 pandemic.
Copyright © 2020 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.rmed.2020.106275
PMCID: PMC7699025
PMID: 33276252 [Indexed for MEDLINE]
Conflict of interest statement: All authors report no conflicts of interest
related to this work. |
http://www.ncbi.nlm.nih.gov/pubmed/36450371 | 1. Eur Respir Rev. 2022 Nov 29;31(166):220099. doi: 10.1183/16000617.0099-2022.
Print 2022 Dec 31.
Inhaled corticosteroids for the treatment of COVID-19.
Bafadhel M(1), Faner R(2), Taillé C(3), Russell REK(4), Welte T(5), Barnes
PJ(6), Agustí A(7).
Author information:
(1)King's Centre for Lung Health, School of Immunology and Microbial Sciences,
Faculty of Life Sciences and Medicine, King's College London, London, UK
mona.bafadhel@kcl.ac.uk.
(2)CIBER Enfermedades Respiratorias, IDIBAPS, Barcelona, Spain.
(3)Department of Pulmonary Diseases, University Hospital Bichat-Claude Bernard,
AP-HP Nord, University of Paris, Paris, France.
(4)King's Centre for Lung Health, School of Immunology and Microbial Sciences,
Faculty of Life Sciences and Medicine, King's College London, London, UK.
(5)Department of Pulmonary and Infectious Diseases, Hannover University School
of Medicine, Hannover, Germany.
(6)National Heart and Lung Institute, Imperial College London, London, UK.
(7)Cátedra de Salud Respiratoria (University of Barcelona), Respiratory
Institute (Hospital Clinic Barcelona), IDIBAPS and CIBERES, Barcelona, Spain.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has
caused severe illness and mortality for millions worldwide. Despite the
development, approval and rollout of vaccination programmes globally to prevent
infection by SARS-CoV-2 and the development of coronavirus disease 2019
(COVID-19), treatments are still urgently needed to improve outcomes. Early in
the pandemic it was observed that patients with pre-existing asthma or COPD were
underrepresented among those with COVID-19. Evidence from clinical studies
indicates that the inhaled corticosteroids (ICS) routinely taken for asthma and
COPD could have had a protective role in preventing severe COVID-19 and,
therefore, may be a promising treatment for COVID-19. This review summarises the
evidence supporting the beneficial effects of ICS on outcomes in patients with
COVID-19 and explores the potential protective mechanisms.
Copyright ©The authors 2022.
DOI: 10.1183/16000617.0099-2022
PMCID: PMC9724831
PMID: 36450371 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest: M. Bafadhel has
unrestricted research grants from AstraZeneca and Roche, and has received
honoraria to her institution for speaker's fees from AstraZeneca, Chiesi, Cipla
and GlaxoSmithKline. She is a scientific adviser to Albus Health and ProAxsis.
Conflict of interest: R. Faner has received research funding, advisory board
fees and lecture fees from AstraZeneca, Chiesi, GlaxoSmithKline and Menarini.
Conflict of interest: C. Taillé has received grants to her institution, advisory
board fees and lecture fees from AstraZeneca, Chiesi, GlaxoSmithKline, Novartis
and Sanofi. Conflict of interest: R.E.K. Russell has received advisory board
fees and lecture fees from AstraZeneca, Chiesi, Cipla and GlaxoSmithKline.
Conflict of interest: T. Welte has received lecture fees from AstraZeneca,
Basilea, Bayer, Berlin Chemie, Biotest, Boehringer Ingelheim, GlaxoSmithKline,
MSD, Novartis, Pfizer, Roche and Sanofi-Aventis, and advisory board fees from
AstraZeneca, Basilea, Bayer, Biotest, Boehringer Ingelheim, Gilead,
GlaxoSmithKline, Janssen, Novartis, Pfizer and Roche. Conflict of interest: P.J.
Barnes has received research funding from AstraZeneca and Boehringer Ingelheim,
and funding for consultancy, scientific advisory boards and talks from
AstraZeneca, Boehringer Ingelheim, Covis, Epi-Endo, Novartis, Pieris and Teva.
Conflict of interest: A. Agustí has unrestricted research grants from
AstraZeneca and GlaxoSmithKline, and has received honoraria for speaker's fees
from AstraZeneca, Chiesi, GlaxoSmithKline, Menarini, Orion Pharma and Zambon. |
http://www.ncbi.nlm.nih.gov/pubmed/32554082 | 1. J Allergy Clin Immunol. 2020 Aug;146(2):307-314.e4. doi:
10.1016/j.jaci.2020.06.010. Epub 2020 Jun 15.
Prevalence and characterization of asthma in hospitalized and nonhospitalized
patients with COVID-19.
Chhiba KD(1), Patel GB(1), Vu THT(2), Chen MM(1), Guo A(1), Kudlaty E(1), Mai
Q(3), Yeh C(4), Muhammad LN(4), Harris KE(1), Bochner BS(1), Grammer LC(1),
Greenberger PA(1), Kalhan R(5), Kuang FL(1), Saltoun CA(1), Schleimer RP(1),
Stevens WW(1), Peters AT(6).
Author information:
(1)Division of Allergy and Immunology, Department of Medicine, Northwestern
University Feinberg School of Medicine, Chicago, Ill.
(2)Division of Epidemiology, Department of Preventive Medicine, Northwestern
University Feinberg School of Medicine, Chicago, Ill.
(3)Department of Feinberg Information and Technology, Northwestern University
Feinberg School of Medicine, Chicago, Ill.
(4)Division of Biostatistics, Department of Preventive Medicine, Northwestern
University Feinberg School of Medicine, Chicago, Ill.
(5)Division of Pulmonary and Critical Care, Department of Medicine, Northwestern
University Feinberg School of Medicine, Chicago, Ill.
(6)Division of Allergy and Immunology, Department of Medicine, Northwestern
University Feinberg School of Medicine, Chicago, Ill. Electronic address:
anjupeters@northwestern.edu.
BACKGROUND: The Centers for Disease Control and Prevention advises that patients
with moderate to severe asthma belong to a high-risk group that is susceptible
to severe coronavirus disease 2019 (COVID-19). However, the association between
asthma and COVID-19 has not been well-established.
OBJECTIVE: The primary objective was to determine the prevalence of asthma among
patients with COVID-19 in a major US health system. We assessed the clinical
characteristics and comorbidities in asthmatic and nonasthmatic patients with
COVID-19. We also determined the risk of hospitalization associated with asthma
and/or inhaled corticosteroid use.
METHODS: Medical records of patients with COVID-19 were searched by a computer
algorithm (March 1 to April 15, 2020), and chart review was used to validate the
diagnosis of asthma and medications prescribed for asthma. All patients had
PCR-confirmed COVID-19. Demographic and clinical features were characterized.
Regression models were used to assess the associations between asthma and
corticosteroid use and the risk of COVID-19-related hospitalization.
RESULTS: Of 1526 patients identified with COVID-19, 220 (14%) were classified as
having asthma. Asthma was not associated with an increased risk of
hospitalization (relative risk, 0.96; 95% CI, 0.77-1.19) after adjusting for
age, sex, and comorbidities. The ongoing use of inhaled corticosteroids did not
increase the risk of hospitalization in a similar adjusted model (relative risk,
1.39; 95% CI, 0.90-2.15).
CONCLUSIONS: Despite a substantial prevalence of asthma in our COVID-19 cohort,
asthma was not associated with an increased risk of hospitalization. Similarly,
the use of inhaled corticosteroids with or without systemic corticosteroids was
not associated with COVID-19-related hospitalization.
Copyright © 2020. Published by Elsevier Inc.
DOI: 10.1016/j.jaci.2020.06.010
PMCID: PMC7295471
PMID: 32554082 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34457096 | 1. Can Respir J. 2021 Aug 24;2021:9621572. doi: 10.1155/2021/9621572. eCollection
2021.
Asthma and COVID-19: Emphasis on Adequate Asthma Control.
Nassoro DD(1)(2), Mujwahuzi L(1)(2), Mwakyula IH(1)(2), Possi MK(3), Lyantagaye
SL(4).
Author information:
(1)Department of Internal Medicine, University of Dar Es Salaam, Mbeya College
of Health and Allied Sciences, Mbeya, Tanzania.
(2)Department of Internal Medicine, Mbeya Zonal Referral Hospital, Mbeya,
Tanzania.
(3)Department of Social Sciences, University of Dar Es Salaam, Mbeya College of
Health and Allied Sciences, Mbeya, Tanzania.
(4)Department of Biochemistry and Molecular Biology, University of Dar Es
Salaam, Mbeya College of Health and Allied Sciences, Mbeya, Tanzania.
Asthmatics are at an increased risk of developing exacerbations after being
infected by respiratory viruses such as influenza virus, parainfluenza virus,
and human and severe acute respiratory syndrome coronaviruses (SARS-CoV).
Asthma, especially when poorly controlled, is an independent risk factor for
developing pneumonia. A subset of asthmatics can have significant defects in
their innate, humoral, and cell-mediated immunity arms, which may explain the
increased susceptibility to infections. Adequate asthma control is associated
with a significant decrease in episodes of exacerbation. Because of their wide
availability and potency to promote adequate asthma control, glucocorticoids,
especially inhaled ones, are the cornerstone of asthma management. The current
COVID-19 pandemic affects millions of people worldwide and possesses mortality
several times that of seasonal influenza; therefore, it is necessary to revisit
this subject. The pathogenesis of SARS-CoV-2, the virus that causes COVID-19,
can potentiate the development of acute asthmatic exacerbation with the
potential to worsen the state of chronic airway inflammation. The relationship
is evident from several studies that show asthmatics experiencing a more adverse
clinical course of SARS-CoV-2 infection than nonasthmatics. Recent studies show
that dexamethasone, a potent glucocorticoid, and other inhaled corticosteroids
significantly reduce morbidity and mortality among hospitalized COVID-19
patients. Hence, while we are waiting for more studies with higher level of
evidence that further narrate the association between COVID-19 and asthma, we
advise clinicians to try to achieve adequate disease control in asthmatics as it
may reduce incidences and severity of exacerbations especially from SARS-CoV-2
infection.
Copyright © 2021 David D. Nassoro et al.
DOI: 10.1155/2021/9621572
PMCID: PMC8397565
PMID: 34457096 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that there are no conflicts
of interest regarding the publication of this article. |
http://www.ncbi.nlm.nih.gov/pubmed/32843175 | 1. Respir Med. 2020 Aug-Sep;170:106045. doi: 10.1016/j.rmed.2020.106045. Epub
2020 May 26.
Use of corticosteroids in asthma and COPD patients with or without COVID-19.
Hasan SS(1), Capstick T(2), Zaidi STR(3), Kow CS(4), Merchant HA(5).
Author information:
(1)Department of Pharmacy, University of Huddersfield, Huddersfield, UK.
Electronic address: s.hasan@hud.ac.uk.
(2)Leeds Teaching Hospitals NHS Trust, St. James's University Hospital, Leeds,
UK.
(3)School of Healthcare, University of Leeds, Leeds, UK.
(4)School of Postgraduate Studies, International Medical University, Kuala
Lumpur, Malaysia.
(5)Department of Pharmacy, University of Huddersfield, Huddersfield, UK.
The potential detrimental effects of steroids on the immune system to fight
viral infections had always been a concern for patients on long term steroids in
chronic conditions. A recent warning from WHO on systemic corticosteroid use
amid COVID-19 raised suspicion among public and healthcare professionals
regarding the safety of steroid use during the SARS-CoV-2 pandemic. The
corticosteroids (inhaled and oral) are commonly prescribed in the management of
asthma and COPD patients and any unsolicited changes in medications use may lead
to potentially severe exacerbations and may risk patient lives. This article
provides a critical review of clinical evidence and offers a detailed discussion
on the safety and efficacy of corticosteroids in asthma and COPD patients, both
with and without COVID-19.
Copyright © 2020 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.rmed.2020.106045
PMCID: PMC7255263
PMID: 32843175 [Indexed for MEDLINE]
Conflict of interest statement: None. |
http://www.ncbi.nlm.nih.gov/pubmed/33114246 | 1. J Clin Med. 2020 Oct 23;9(11):3406. doi: 10.3390/jcm9113406.
Inhaled Corticosteroids and COVID-19 Risk and Mortality: A Nationwide Cohort
Study.
Choi JC(1), Jung SY(2), Yoon UA(2), You SH(2), Kim MS(2), Baek MS(1), Jung
JW(1), Kim WY(1).
Author information:
(1)Department of Internal Medicine, Chung-Ang University Hospital, Chung-Ang
University College of Medicine, Seoul 06973, Korea.
(2)College of Pharmacy, Chung-Ang University, Seoul 06973, Korea.
Inhaled corticosteroids (ICS) could increase both the risk of coronavirus
disease 2019 (COVID-19) and experiencing poor outcomes. To compare the clinical
outcomes between ICS users and nonusers, COVID-19-related claims in the Korean
Health Insurance Review and Assessment database were evaluated. To evaluate
susceptibility to COVID-19 among patients with COPD or asthma, a nested
case-control study was performed using the same database. In total, 7341
patients were confirmed to have COVID-19, including 114 ICS users and 7227
nonusers. Among 5910 patients who were hospitalized, death was observed for 9%
of ICS users and 4% of nonusers. However, this association was not significant
when adjusted for age, sex, region, comorbidities, and hospital type (aOR, 0.94;
95% CI, 0.43-2.07). The case-control analysis of COPD compared 640 cases with
COVID-19 to 2560 matched controls without COVID-19, and the analysis of asthma
compared 90 cases with COVID-19 to 360 matched controls without COVID-19. Use of
ICS was not significantly associated with COVID-19 among patients with COPD
(aOR, 1.02; 95% CI, 0.46-2.25) or asthma (aOR, 0.38; 95% CI, 0.13-1.17). Prior
ICS use was not significantly associated with COVID-19 in patients with COPD or
asthma, nor with clinical outcomes among patients with COVID-19.
DOI: 10.3390/jcm9113406
PMCID: PMC7690894
PMID: 33114246
Conflict of interest statement: The authors declare no conflicts of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/34295392 | 1. Breathe (Sheff). 2021 Mar;17(1):200275. doi: 10.1183/20734735.0275-2020.
Does inhaled corticosteroid use affect the risk of
COVID-19-related death?
Jordan A(1), Sivapalan P(1), Jensen JU(1).
Author information:
(1)Dept of Internal Medicine, Respiratory Medicine Section, Herlev and Gentofte
Hospital, University of Copenhagen, Hellerup, Denmark.
ICS does not seem to protect against COVID-19-related mortality, but more data
is needed to determine whether it is harmful. Due to its known and important
benefits ICS should be prescribed as usual for both asthma and COPD.
https://bit.ly/3pWVimX.
Copyright ©ERS 2021.
DOI: 10.1183/20734735.0275-2020
PMCID: PMC8291911
PMID: 34295392
Conflict of interest statement: Conflict of interest: A. Jordan has nothing to
disclose. Conflict of interest: P. Sivapalan reports personal fees from
Boehringer Ingelheim, outside the submitted work. Conflict of interest: J-U.
Jensen has nothing to disclose. |
http://www.ncbi.nlm.nih.gov/pubmed/32348052 | 1. Rev Med Suisse. 2020 Apr 29;16(N° 691-2):852-854.
[Drugs that aggravate the course of COVID-19 : really ?].
[Article in French; Abstract available in French from the publisher]
Rothuizen LE(1), Livio F(1), Buclin T(1).
Author information:
(1)Service de pharmacologie clinique, Département des laboratoires, CHUV, 1011
Lausanne.
The safety of NSAIDs, corticosteroids and renin-angiotensin inhibitors in
COVID-19 is challenged. NSAIDs may interfere with the defense process against
viral infection and are best avoided. Systemic corticosteroids have not shown
benefit in viral infection, including other coronavirus; thus they should be
avoided, unless prescribed for another indication. The benefit-risk ratio is
however clearly in favor of continuing inhaled corticosteroids in patients with
asthma or COPD. ACE inhibitors and sartans upregulate the expression of
angiotensin-converting enzyme 2 (ACE2), the pulmonary receptor for SARS-CoV-2.
Any possible clinical impact of these treatments on COVID-19 infection remains
to be clarified; in the meantime, they should be continued.
Publisher: La sécurité des AINS, corticoïdes et antihypertenseurs agissant sur
le système rénine-angiotensine lors d’infection à COVID-19 est mise en question.
Les AINS pourraient interférer avec le processus de défense face à une infection
virale ; ils sont donc plutôt à éviter. Les corticoïdes systémiques n’ont pas
montré de bénéfice lors d’infections virales, y compris à d’autres coronavirus ;
ils sont à éviter, sauf si prescrits pour une autre indication. Le rapport
bénéfice/risque est en revanche clairement en faveur de la poursuite des
corticostéroïdes inhalés chez les asthmatiques ou BPCO. Les IEC et les sartans
modulent l’expression de l’enzyme de conversion de l’angiotensine 2 (ACE2),
récepteur pulmonaire du SARS-CoV-2. L’impact clinique de ces traitements sur
l’infection à COVID-19 reste à préciser ; en attendant, ils sont à poursuivre.
PMID: 32348052 [Indexed for MEDLINE]
Conflict of interest statement: Les auteurs n’ont déclaré aucun conflit
d’intérêts en relation avec cet article. |
http://www.ncbi.nlm.nih.gov/pubmed/33357281 | 1. Allergy Asthma Proc. 2021 Jan 1;42(1):93-96. doi: 10.2500/aap.2021.42.200111.
Epub 2020 Dec 23.
Considerations for asthma management and viral transmission in the era of
COVID-19.
Pitlick MM(1), Joshi AY(1).
Author information:
(1)From the Division of Allergic Disease, Department of Medicine, Mayo Clinic,
Rochester, Minnesota; and.
Background: As the global COVID-19 pandemic has unfolded, there has been much
debate surrounding the optimal management of patients with asthma who are at
risk of or contract COVID-19, whether asthma and steroids are risk factors for
severe COVID-19, and how transmissible the virus is among children. Objective:
The objective of this study is to provide allergists and other clinicians with
pearls pertaining to the management of patients with asthma in the setting of
the COVID-19 pandemic and to provide some information regarding the risk of
transmission among the pediatric population. Methods: Utilizing the case of one
of our own patients with asthma who developed COVID-19 as context, we review the
recent literature discussing the risk of COVID-19 in patients with asthma, the
management of asthma medications in the time of the pandemic, and the risk of
viral transmission. Results: Despite initial reports that asthma was a risk
factor for developing severe COVID-19, subsequent investigation has shown that
this is likely not true. Additionally, the use of systemic or inhaled
glucocorticoids does not appear to increase the risk of severe COVID-19, but
there is no evidence guiding the use of biologic therapy. There is conflicting
evidence regarding the ability of children to transmit the virus. Conclusion: We
provide pearls that asthma does not appear to be associated with an increased
risk of COVID-19 and continued use of inhaled corticosteroids appears to be
safe. While there is no evidence guiding the use of biologic therapies, a recent
position paper suggests that they should be continued unless a patient contracts
COVID-19, at which point they should be held until clinical recovery occurs.
DOI: 10.2500/aap.2021.42.200111
PMID: 33357281 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33844996 | 1. Lancet Respir Med. 2021 Jul;9(7):763-772. doi: 10.1016/S2213-2600(21)00160-0.
Epub 2021 Apr 9.
Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2,
open-label, randomised controlled trial.
Ramakrishnan S(1), Nicolau DV Jr(2), Langford B(3), Mahdi M(3), Jeffers H(3),
Mwasuku C(3), Krassowska K(3), Fox R(4), Binnian I(5), Glover V(6), Bright S(7),
Butler C(8), Cane JL(3), Halner A(9), Matthews PC(10), Donnelly LE(11), Simpson
JL(12), Baker JR(11), Fadai NT(13), Peterson S(14), Bengtsson T(14), Barnes
PJ(11), Russell REK(15), Bafadhel M(16).
Author information:
(1)Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK;
National Institute for Health Research (NIHR), Oxford Biomedical Research
Centre, Oxford, UK; School of Medical and Health Sciences, Edith Cowan
University, Perth, WA, Australia.
(2)Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK;
UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD,
Australia; School of Mathematical Sciences, Queensland University of Technology,
Brisbane, QLD, Australia.
(3)Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK;
National Institute for Health Research (NIHR), Oxford Biomedical Research
Centre, Oxford, UK.
(4)Bicester Health Centre, Bicester, UK; NIHR, Thames Valley and South Midlands,
UK.
(5)Eynsham Medical Group, Eynsham, UK.
(6)White Horse Medical Practice, Faringdon, UK.
(7)Windrush Medical Practice, Witney, UK.
(8)Nuffield Department of Primary Health Care Sciences, University of Oxford,
Oxford, UK.
(9)Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
(10)Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK;
Department of Infectious Diseases and Microbiology, Oxford University Hospitals
NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK.
(11)National Heart and Lung Institute, Imperial College, London, UK.
(12)Priority Research Centre for Healthy Lungs, School of Medicine and Public
Health, University of Newcastle, NSW, Australia.
(13)School of Mathematical Sciences, University of Nottingham, Nottingham, UK.
(14)STATMIND, Lund, Sweden.
(15)Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK;
National Institute for Health Research (NIHR), Oxford Biomedical Research
Centre, Oxford, UK; Southernhealth NHS Foundation Trust, Hampshire, UK.
(16)Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK;
National Institute for Health Research (NIHR), Oxford Biomedical Research
Centre, Oxford, UK. Electronic address: mona.bafadhel@ndm.ox.ac.uk.
Erratum in
Lancet Respir Med. 2021 Jun;9(6):e55. doi: 10.1016/S2213-2600(21)00181-8.
Comment in
Lancet Respir Med. 2021 Jul;9(7):682-683. doi:
10.1016/S2213-2600(21)00171-5.
Lancet Respir Med. 2021 Jul;9(7):e59. doi: 10.1016/S2213-2600(21)00215-0.
Lancet Respir Med. 2021 Jul;9(7):e60. doi: 10.1016/S2213-2600(21)00217-4.
Lancet Respir Med. 2021 Jul;9(7):e58. doi: 10.1016/S2213-2600(21)00211-3.
Lancet Respir Med. 2021 Jul;9(7):e61. doi: 10.1016/S2213-2600(21)00212-5.
Pneumologie. 2021 Jun;75(6):418-420. doi: 10.1055/a-1488-5373.
CJEM. 2021 Sep;23(5):611-612. doi: 10.1007/s43678-021-00154-3.
BACKGROUND: Multiple early reports of patients admitted to hospital with
COVID-19 showed that patients with chronic respiratory disease were
significantly under-represented in these cohorts. We hypothesised that the
widespread use of inhaled glucocorticoids among these patients was responsible
for this finding, and tested if inhaled glucocorticoids would be an effective
treatment for early COVID-19.
METHODS: We performed an open-label, parallel-group, phase 2, randomised
controlled trial (Steroids in COVID-19; STOIC) of inhaled budesonide, compared
with usual care, in adults within 7 days of the onset of mild COVID-19 symptoms.
The trial was done in the community in Oxfordshire, UK. Participants were
randomly assigned to inhaled budsonide or usual care stratified for age (≤40
years or >40 years), sex (male or female), and number of comorbidities (≤1 and
≥2). Randomisation was done using random sequence generation in block
randomisation in a 1:1 ratio. Budesonide dry powder was delivered using a
turbohaler at a dose of 400 μg per actuation. Participants were asked to take
two inhalations twice a day until symptom resolution. The primary endpoint was
COVID-19-related urgent care visit, including emergency department assessment or
hospitalisation, analysed for both the per-protocol and intention-to-treat (ITT)
populations. The secondary outcomes were self-reported clinical recovery
(symptom resolution), viral symptoms measured using the Common Cold Questionnare
(CCQ) and the InFLUenza Patient Reported Outcome Questionnaire (FLUPro), body
temperature, blood oxygen saturations, and SARS-CoV-2 viral load. The trial was
stopped early after independent statistical review concluded that study outcome
would not change with further participant enrolment. This trial is registered
with ClinicalTrials.gov, NCT04416399.
FINDINGS: From July 16 to Dec 9, 2020, 167 participants were recruited and
assessed for eligibility. 21 did not meet eligibility criteria and were
excluded. 146 participants were randomly assigned-73 to usual care and 73 to
budesonide. For the per-protocol population (n=139), the primary outcome
occurred in ten (14%) of 70 participants in the usual care group and one (1%) of
69 participants in the budesonide group (difference in proportions 0·131, 95% CI
0·043 to 0·218; p=0·004). For the ITT population, the primary outcome occurred
in 11 (15%) participants in the usual care group and two (3%) participants in
the budesonide group (difference in proportions 0·123, 95% CI 0·033 to 0·213;
p=0·009). The number needed to treat with inhaled budesonide to reduce COVID-19
deterioration was eight. Clinical recovery was 1 day shorter in the budesonide
group compared with the usual care group (median 7 days [95% CI 6 to 9] in the
budesonide group vs 8 days [7 to 11] in the usual care group; log-rank test
p=0·007). The mean proportion of days with a fever in the first 14 days was
lower in the budesonide group (2%, SD 6) than the usual care group (8%, SD 18;
Wilcoxon test p=0·051) and the proportion of participants with at least 1 day of
fever was lower in the budesonide group when compared with the usual care group.
As-needed antipyretic medication was required for fewer proportion of days in
the budesonide group compared with the usual care group (27% [IQR 0-50] vs 50%
[15-71]; p=0·025) Fewer participants randomly assigned to budesonide had
persistent symptoms at days 14 and 28 compared with participants receiving usual
care (difference in proportions 0·204, 95% CI 0·075 to 0·334; p=0·003). The mean
total score change in the CCQ and FLUPro over 14 days was significantly better
in the budesonide group compared with the usual care group (CCQ mean difference
-0·12, 95% CI -0·21 to -0·02 [p=0·016]; FLUPro mean difference -0·10, 95% CI
-0·21 to -0·00 [p=0·044]). Blood oxygen saturations and SARS-CoV-2 load,
measured by cycle threshold, were not different between the groups. Budesonide
was safe, with only five (7%) participants reporting self-limiting adverse
events.
INTERPRETATION: Early administration of inhaled budesonide reduced the
likelihood of needing urgent medical care and reduced time to recovery after
early COVID-19.
FUNDING: National Institute for Health Research Biomedical Research Centre and
AstraZeneca.
Copyright © 2021 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S2213-2600(21)00160-0
PMCID: PMC8040526
PMID: 33844996 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests SR reports grants and
non-financial support from the NIHR Biomedical Research Centre, during the
conduct of the study; and non-financial support from AstraZeneca, personal fees
from Australian Government Research Training Program, outside the submitted
work. HJ reports personal fees from AstraZeneca, outside of the submitted work.
CB reports grants from NIHR, Roche Molecular Diagnostics, Janssen
Pharmaceuticals, and the NIHR for research related to diagnostics and
infections. CB has received personal fees from Pfizer, Roche Diagnostics, and
Janssen Pharmaceuticals, outside of the submitted work. LED reports grants from
AstraZeneca, and Boehringer Ingelheim, outside of the submitted work. SP reports
personal fees from AstraZeneca, outside of the submitted work. TB reports
personal fees from AstraZeneca, outside of the submitted work. PJB reports
grants and personal fees from AstraZeneca and Boehringer Ingelheim, and personal
fees from Teva and Covis, during the conduct of the study. REKR reports grants
from AstraZeneca, and personal fees from Boehringer Ingelheim, Chiesi UK, and
GlaxoSmithKline, during the conduct of the study. MB reports grants from
AstraZeneca, personal fees from AstraZeneca, Chiesi, GlaxoSmithKline, and
scientific adviser to Albus Health and ProAxsis outside of the submitted work.
DVNJr, BL, MM, CM, KK, RF, IB, VG, SB, JLC, AH, PCM, JLS, JRB, and NTF declare
no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/33183113 | 1. Expert Rev Respir Med. 2021 Apr;15(4):561-568. doi:
10.1080/17476348.2021.1850275. Epub 2020 Dec 3.
Reduced risk of COVID-19 hospitalization in asthmatic and COPD patients: a
benefit of inhaled corticosteroids?
Rogliani P(1), Lauro D(2), Di Daniele N(2), Chetta A(3), Calzetta L(3).
Author information:
(1)Unit of Respiratory Medicine, Department of Experimental Medicine, University
of Rome "Tor Vergata", Rome, Italy.
(2)Department of Systems Medicine, University of Rome "Tor Vergata", Rome,
Italy.
(3)Department of Medicine and Surgery, Respiratory Disease and Lung Function
Unit, University of Parma, Parma, Italy.
Background: The comorbidities and clinical signs of coronavirus disease 2019
(COVID-19) patients have been reported mainly as descriptive statistics, rather
than quantitative analysis even in very large investigations. The aim of this
study was to identify specific patients' characteristics that may modulate
COVID-19 hospitalization risk.Research design and methods: A pooled analysis was
performed on high-quality epidemiological studies to quantify the prevalence (%)
of comorbidities and clinical signs in hospitalized COVID-19 patients. Pooled
data were used to calculate the relative risk (RR) of specific comorbidities by
matching the frequency of comorbidities in hospitalized COVID-19 patients with
those of general population.Results: The most frequent comorbidities were
hypertension, diabetes mellitus, and cardiovascular and/or cerebrovascular
diseases. The RR of COVID-19 hospitalization was significantly (P < 0.05)
reduced in patients with asthma (0.86, 0.77-0.97) or chronic obstructive
pulmonary disease (COPD) (0.46, 0.40-0.52). The most frequent clinical signs
were fever and cough.Conclusion: The clinical signs of hospitalized COVID-19
patients are similar to those of other infective diseases. Patients with asthma
or COPD were at lower hospitalization risk. This paradoxical evidence could be
related with the protective effect of inhaled corticosteroids that are
administered worldwide to most asthmatic and COPD patients.
DOI: 10.1080/17476348.2021.1850275
PMCID: PMC7752139
PMID: 33183113 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33248363 | 1. Respir Med. 2021 Jan;176:106236. doi: 10.1016/j.rmed.2020.106236. Epub 2020
Nov 19.
Guidance on nebulization during the current COVID-19 pandemic.
Cazzola M(1), Ora J(2), Bianco A(3), Rogliani P(4), Matera MG(5).
Author information:
(1)Department of Experimental Medicine, University of Rome "Tor Vergata", Rome,
Italy. Electronic address: mario.cazzola@uniroma2.it.
(2)Respiratory Diseases Unit, "Tor Vergata" University Hospital, Rome, Italy.
(3)Department of Translational Medical Sciences, University of Campania "Luigi
Vanvitelli"/Monaldi Hospital, Naples, Italy.
(4)Department of Experimental Medicine, University of Rome "Tor Vergata", Rome,
Italy; Respiratory Diseases Unit, "Tor Vergata" University Hospital, Rome,
Italy.
(5)Department of Experimental Medicine, University of Campania "Luigi
Vanvitelli", Naples, Italy.
Awareness of the risk of airborne transmission of SARS-CoV-2 makes patients
hesitant about using inhaled medications that are considered as a potential
source of viral transmission and immunosuppression. However, patients with
asthma or COPD should continue all prescribed inhaled medications. Apparently,
inhalers, including pMDIs, DPIs, or SMIs, have a low risk of contamination
although characteristics of drug formulation can precipitate cough, whereas some
researchers do not rule out the probability that nebulizer treatments may
increase the risk of infection transmission via droplet nuclei and aerosols.
Considering that aerosol therapy generates fugitive emissions that are not
inhaled by the patient and are released from the device during expiration,
several international professional bodies have provided recommendations for drug
delivery via inhalers and in particular, nebulizers. Unfortunately, these
recommendations are often in conflict with each other and do not clarify whether
it is appropriate to use nebulizers during this COVID-19 pandemic. Considering
what is available in literature, there are no known infection-related hazards to
an uninfected patient and also a patient with COVID-19 that preclude the use of
a nebulizer at home, but it fundamental that all patients, regardless of whether
or not suffering from COVID-19, always follow some practical advices.
Copyright © 2020 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.rmed.2020.106236
PMCID: PMC7676318
PMID: 33248363 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no known
competing financial interests or personal relationships that could have appeared
to influence the work reported in this paper. |
http://www.ncbi.nlm.nih.gov/pubmed/35801604 | 1. Pol Merkur Lekarski. 2022 Jun 24;50(297):195-197.
Treatment of patients with asthma during COVID-19.
Płusa T(1).
Author information:
(1)Faculty of Medicine of Lazarski University in Warsaw, Poland.
Good management of patients with bronchial asthma protects against SARS-CoV-2
infection, which is associated with the activity limiting the virus penetration
into the respiratory epithelial cells. A relationship between asthma
exacerbation and SARS-CoV-2 infection has not yet been demonstrated. The
available recommendations state that patients with asthma should use inhaled
glucocorticosteroids (GCS) on a regular basis. In the case of exacerbation of
asthma symptoms, it is necessary to administer higher doses of inhaled GCSs and
to quickly add systemic GCSs, mainly methylprednisolone. Treatment with
biological preparations does not increase the risk of SARS-CoV-2 infection, and
is effective in reducing the number of asthma exacerbations.
© 2022 MEDPRESS.
PMID: 35801604 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34922224 | 1. J Infect Public Health. 2022 Jan;15(1):56-64. doi: 10.1016/j.jiph.2021.12.003.
Epub 2021 Dec 8.
The effects of the antecedent use of inhaled steroid on the clinical course of
COVID-19: A retrospective study of asthmatic patients.
Alakeel YS(1), Alharbi EF(2), Alhaidal HA(3), Jumaa AM(4), Albaiahy LK(3),
Alsagami NS(5), Alshahrani SA(5).
Author information:
(1)College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences,
Riyadh, Saudi Arabia; King Abdullah International Medical Research Center,
Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia; Pharmaceutical
Care Department, King Abdulaziz Medical City, Ministry of National Guard Health
Affairs, Riyadh, Saudi Arabia. Electronic address: alaqeely@ksau-hs.edu.sa.
(2)King Abdullah International Medical Research Center, Ministry of National
Guard Health Affairs, Riyadh, Saudi Arabia; College of Applied Medical Sciences,
Respiratory therapy Department, King Saud bin Abdulaziz University for Health
Sciences, Riyadh, Saudi Arabia. Electronic address: rt.ebtihalfahad@gmail.com.
(3)College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences,
Riyadh, Saudi Arabia; King Abdullah International Medical Research Center,
Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia.
(4)King Abdullah International Medical Research Center, Ministry of National
Guard Health Affairs, Riyadh, Saudi Arabia; Respiratory Services, King Abdulaziz
Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia.
(5)King Abdullah International Medical Research Center, Ministry of National
Guard Health Affairs, Riyadh, Saudi Arabia; College of Applied Medical Sciences,
Respiratory therapy Department, King Saud bin Abdulaziz University for Health
Sciences, Riyadh, Saudi Arabia.
BACKGROUND: There is conflicting evidence regarding the effect of asthma and its
different therapeutic options on COVID-19 severity and the clinical outcomes.
AIM: This study aimed to investigate the relationship between using inhaled
corticosteroids (ICS) by asthmatic patients and the severity of COVID-19.
MATERIALS AND METHODS: This retrospective observational study was conducted from
March 15 to October 23, 2020 and included data of all COVID-19 asthmatic
patients (n = 287) at King Abdulaziz Medical City. Twelve patients were excluded
due to poor medication history documentation or using ICS for non-asthma
indication. Ordinal logistic regression was used to determine the clinical
variables that affect COVID-19 severity. The clinical outcomes of ICS and
non-ICS users were compared.
RESULTS: Of the sample (n = 275), 198 (72%) were using ICS therapy. No
significant difference was found between ICS and non-ICS users in disease
severity (P = 0.12), mortality (P = 0.45), ICU admission (P = 0.78), and the
occurrence of complications. However, the number of days on ventilation were
significantly increased in ICS users (P = 0.006). Being prescribed the ICS/LABA
combination (adj OR: 0.72 [0.15,1.2]; P = 0.021), being hypertensive (adj OR:
0.98 [0.28,1.6]; P = 0.006), having cancer (adj OR: 1.49 [0.12, 2.8];
P = 0.033), or having diabetes (adj OR: 0.75 [0.09, 1.4]; P = 0.024) could not
increase the risk for more severe disease.
CONCLUSION: Overall, ICS therapy did not alter the COVID-19 severity or
mortality in asthmatic patients. The continued use of ICS during the pandemic
should be encouraged to prevent asthma exacerbations.
Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/j.jiph.2021.12.003
PMCID: PMC8653412
PMID: 34922224 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34081722 | 1. PLoS One. 2021 Jun 3;16(6):e0252576. doi: 10.1371/journal.pone.0252576.
eCollection 2021.
Inhaled corticosteroids do not adversely impact outcomes in COVID-19 positive
patients with COPD: An analysis of Cleveland Clinic's COVID-19 registry.
Sen P(1), Majumdar U(1), Zein J(1)(2), Hatipoğlu U(1), Attaway AH(1).
Author information:
(1)Respiratory Institute, Cleveland Clinic, Cleveland, Ohio, United States of
America.
(2)Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States
of America.
Inhaled Corticosteroids (ICS) are commonly prescribed to patients with severe
COPD and recurrent exacerbations. It is not known what impact ICS cause in terms
of COVID-19 positivity or disease severity in COPD. This study examined 27,810
patients with COPD from the Cleveland Clinic COVID-19 registry between March 8th
and September 16th, 2020. Electronic health records were used to determine
diagnosis of COPD, ICS use, and clinical outcomes. Multivariate logistic
regression was used to adjust for demographics, month of COVID-19 testing, and
comorbidities known to be associated with increased risk for severe COVID-19
disease. Amongst the COPD patients who were tested for COVID-19, 44.1% of those
taking an ICS-containing inhaler tested positive for COVID-19 versus 47.2% who
tested negative for COVID-19 (p = 0.033). Of those who tested positive for
COVID-19 (n = 1288), 371 (28.8%) required hospitalization. In-hospital outcomes
were not significantly different when comparing ICS versus no ICS in terms of
ICU admission (36.8% [74/201] vs 31.2% [53/170], p = 0.30), endotracheal
intubation (21.9% [44/201] vs 16.5% [28/170], p = 0.24), or mortality (18.4%
[37/201] vs 20.0% [34/170], p = 0.80). Multivariate logistic regression
demonstrated no significant differences in hospitalization (adj OR 1.12, CI:
0.90-1.38), ICU admission (adj OR: 1.31, CI: 0.82-2.10), need for mechanical
ventilation (adj OR 1.65, CI: 0.69-4.02), or mortality (OR: 0.80, CI:
0.43-1.49). In conclusion, ICS therapy did not increase COVID-19 related
healthcare utilization or mortality outcome in patients with COPD followed at
the Cleveland Clinic health system. These findings should encourage clinicians
to continue ICS therapy for COPD patients during the COVID-19 pandemic.
DOI: 10.1371/journal.pone.0252576
PMCID: PMC8174679
PMID: 34081722 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/34112029 | 1. J Asthma. 2022 Aug;59(8):1501-1508. doi: 10.1080/02770903.2021.1941093. Epub
2021 Jun 21.
Asthma in the era of SARS CoV-2 virus.
Bakakos A(1), Krompa A(1).
Author information:
(1)School of Health Sciences, 1st University Department Of Respiratory Medicine,
National and Kapodistrian University of Athens, Athens, Greece.
OBJECTIVES: It is well established in international literature that respiratory
viruses can trigger asthma exacerbations. However, not all viruses affect
patients in the same manner and extent. The pandemic of the SARS CoV-2 virus has
brought interest to study the association of this novel virus on patients with
mild-moderate and severe asthma in terms of susceptibility, severity and
treatment.
DATA SOURCES – STUDY SELECTION: We performed an extensive search of current
literature in the databases PubMed, Scopus and Google Scholar for original
articles. We decided to include all types of articles, except for case studies,
published until the end of February 2021 focusing on the effects of COVID-19 on
the respiratory system and the main treatment recommendations up to date for
patients with bronchial asthma.
RESULTS: Until now there is no clear evidence that asthmatics have a higher risk
of experiencing exacerbations when infected, nor higher mortality rates than the
general population. Nevertheless, our knowledge on molecular pathways behind
asthma phenotypes in the past decades is growing, and it underlines the need to
predict the unique response each patient may have to infection from the novel
coronavirus. It is not clear yet if certain sub-populations of asthmatics are at
higher risk than others.
CONCLUSION: Despite the lack of evidence for higher susceptibility and/or
mortality in relation to COVID-19, all asthmatic patients, whether treated with
inhaled bronchodilators/corticosteroids or even biologics, should maintain their
controller therapy without making any alterations.
DOI: 10.1080/02770903.2021.1941093
PMID: 34112029 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34926333 | 1. Immunotargets Ther. 2021 Dec 11;10:419-430. doi: 10.2147/ITT.S342636.
eCollection 2021.
Understanding and Managing Severe Asthma in the Context of COVID-19.
Kong-Cardoso B(1), Ribeiro A(2), Aguiar R(1), Pité H(1), Morais-Almeida M(1).
Author information:
(1)Allergy Center, CUF Descobertas Hospital and CUF Tejo Hospital, Lisbon,
Portugal.
(2)Pneumology Department, Centro Hospitalar Barreiro Montijo, Barreiro,
Portugal.
Coronavirus disease 2019 (COVID-19) continues to spread across the world. Since
the beginning of the pandemic, the question of whether asthma is a risk factor
for getting the infection or for poor outcomes motivated a great debate. In the
field of severe asthma and its treatment during COVID-19 pandemic, several
issues are also pending. A literature review focused on the management of severe
asthma patients in the context of COVID-19 is performed. The available evidence
suggests that severe asthma patients do not have an increased risk of poor
COVID-19 outcomes and that it is safe to treat asthmatic patients with inhaled
corticosteroids (ICS) and biologics during the pandemic, even though some
studies indicate that high doses of ICS may predispose to COVID-19. The chronic
use of oral corticosteroid (OCS) might be associated with poor COVID-19
outcomes, although there is no complete agreement. There is very limited
evidence concerning the use of triple therapy for asthma in the context of this
pandemic. Ultimately, severe asthma patients should maintain their medication
during the COVID-19 pandemic, including biologic agents. More studies are needed
to address the role of asthma medications and asthma's different phenotypes on
the incidence and course of COVID-19.
© 2021 Kong-Cardoso et al.
DOI: 10.2147/ITT.S342636
PMCID: PMC8675091
PMID: 34926333
Conflict of interest statement: The authors report no conflicts on interest in
this work. |
http://www.ncbi.nlm.nih.gov/pubmed/35651781 | 1. Ther Adv Hematol. 2022 May 27;13:20406207221093980. doi:
10.1177/20406207221093980. eCollection 2022.
Zanubrutinib in lymphoproliferative disorders: a comprehensive review.
Muñoz J(1), Wang Y(2), Jain P(3), Wang M(3).
Author information:
(1)Program Director, Lymphoma, Mayo Clinic, 5881 E. Mayo Boulevard, Phoenix, AZ
85054, USA.
(2)Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA.
(3)The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
The availability of Bruton tyrosine kinase (BTK) inhibitors has brought about a
paradigm shift in the treatment of patients with B-cell lymphomas and chronic
lymphocytic leukemia. BTK was clinically validated as a target by the efficacy
of the first-in-class inhibitor ibrutinib. The extended survival conferred by
BTK inhibitors has brought long-term tolerability to the foreground. To minimize
toxicities thought to be attributable to off-target kinase inhibition, a next
generation of BTK inhibitors with greater selectivity was developed. In the
United States, zanubrutinib, a next-generation BTK inhibitor, has been approved
for treating adults with mantle cell lymphoma who have received at least one
prior therapy, for adults with Waldenström macroglobulinemia, and for adults
with relapsed or refractory marginal zone lymphoma who have received at least
one anti-CD20-based therapy. Because few head-to-head comparative trials of BTK
inhibitors have so far been reported, no BTK 'inhibitor of choice' can be
identified. Zanubrutinib has promising efficacy in its approved indications and
appears to have reduced cardiac toxicities, particularly atrial fibrillation,
which may influence the choice of BTK inhibitor treatment by prescribers.
Further studies are needed to inform on optimal treatment sequencing of
zanubrutinib and its combination with other agents. Here, we summarize existing
clinical evidence for its efficacy and safety in mantle cell lymphoma,
Waldenström macroglobulinemia, marginal zone lymphoma, chronic lymphocytic
leukemia/small lymphocytic lymphoma, and other B-lymphoproliferative
indications.
PLAIN LANGUAGE SUMMARY: Zanubrutinib is a drug that was shown to effectively
treat cancer of B cells without causing excessive serious side effects Patients
with certain B-cell malignancies (cancers of white blood cells) benefit from
treatment with Bruton tyrosine kinase (BTK) inhibitors, drugs that block the BTK
protein and keep cancer from growing and spreading. Patients experience extended
survival with ibrutinib, the first-generation BTK inhibitor approved by US Food
and Drug Administration (FDA); however, one in five patients quit treatment
because of harmful side effects. Ibrutinib-related side effects such as
increased risk of bleeding, atrial fibrillation (abnormal heart rhythm), and
high blood pressure are thought to be caused by ibrutinib blocking other
proteins besides the intended target protein BTK. To reduce these side effects,
zanubrutinib, a next-generation BTK inhibitor, was designed to block BTK more
specifically than ibrutinib. Results of clinical studies on zanubrutinib
treatment appear promising in patients with several types of B-cell
malignancies, including mantle cell lymphoma (MCL), Waldenström
macroglobulinemia (WM), marginal zone lymphoma (MZL), chronic lymphocytic
leukemia, and small lymphocytic lymphoma. There are not yet enough clinical data
to determine which BTK inhibitor is most effective in treating B-cell
malignancies without causing harmful side effects. Early data from the phase 3
ALPINE clinical study suggest that zanubrutinib works better than ibrutinib, and
fewer patients experience side effects and quit treatment. Zanubrutinib is
currently approved for use for treatment of adult patients with MCL who have
received at least one prior therapy, for adults with WM, and for adults with MZL
who have received at least one anti-CD20-based therapy.
© The Author(s), 2022.
DOI: 10.1177/20406207221093980
PMCID: PMC9150264
PMID: 35651781
Conflict of interest statement: Conflict of interest statement: The authors
declared the following potential conflicts of interest with respect to the
research, authorship, and/or publication of this article: JM reports consultancy
role with, research funding from, and speakers’ bureau for Pharmacyclics, Bayer,
Gilead/Kite Pharma, Janssen, and Celgene; consultancy role with Pfizer, Alexion,
Fosunkite, Innovent, Debiopharm, Epizyme, Karyopharm, and Genmab; consultancy
role with Juno/Celgene; consultancy role with and speakers’ bureau for Bristol
Myers Squibb, BeiGene; consultancy role with, honoraria from, and speakers’
bureau for Kyowa; consultancy role with, research funding from, honoraria from,
and speakers’ bureau for Seattle Genetics; research funding from Merck, Portola,
Incyte, and Millennium; research funding from and speakers’ bureau for
Genentech; speakers’ bureau for Acrotech/Aurobindo, Verastem, AstraZeneca,
Roche, and AbbVie. YW reports research funding from, and advisory role with
Incyte and Loxo Oncology; research funding from InnoCare, Novartis, and
Genentech; advisory role with Eli Lilly and TG therapeutics. PJ reports
consultancy role with Eli Lilly, Incyte, Kite, research funding from
AstraZeneca. MW reports research funding and honoraria from Acerta Pharma;
consultancy role with, research funding, and honoraria from AstraZeneca,
BeiGene, Janssen, and Kite Pharma; honoraria from Anticancer Association, CAHON,
Chinese Medical Association, Clinical Care Options, Dava Oncology, Hebei Cancer
Prevention Federation, Imbruvica, Imedex, Moffit Cancer Center, Mumbai
Hematology Group, Newbridge Pharmaceuticals, OMI, Physicians Education Resources
(PER), Scripps, and The First Affiliated Hospital of Zhejiang University;
consultancy role with Bayer Healthcare, CSTone, DTRM Biopharma (Cayman) Limited,
and Genentech; research funding from BioInvent, Celgene, and Molecular
Templates; consultancy role with and honoraria from Epizyme and Miltenyi
Biomedicine GmbH; consultancy role with and research funding from InnoCare,
Juno, Loxo Oncology, Oncternal, Pharmacyclics, and VelosBio. |
http://www.ncbi.nlm.nih.gov/pubmed/34420980 | 1. J Neuromuscul Dis. 2022;9(1):39-52. doi: 10.3233/JND-210665.
A Combined Prospective and Retrospective Comparison of Long-Term Functional
Outcomes Suggests Delayed Loss of Ambulation and Pulmonary Decline with
Long-Term Eteplirsen Treatment.
Mitelman O(1), Abdel-Hamid HZ(2), Byrne BJ(3), Connolly AM(4), Heydemann P(5),
Proud C(6), Shieh PB(7), Wagner KR(8), Dugar A(1), Santra S(1), Signorovitch
J(9), Goemans N(10); investigators from the LNMRC Natural History study;
McDonald CM(11); investigators from the CINRG Duchenne National History Study;
Mercuri E(12); investigators from The DMD Italian Group; Mendell JR(4).
Author information:
(1)Sarepta Therapeutics, Inc., Cambridge, MA, USA.
(2)UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
(3)University of Florida, Gainesville, FL, USA.
(4)Nationwide Children's Hospital, The Ohio State University College of
Medicine, Columbus, OH, USA.
(5)Rush University Medical Center, Chicago, IL, USA.
(6)Children's Hospital of The King's Daughters, Norfolk, VA, USA.
(7)University of California Los Angeles, Los Angeles, CA, USA.
(8)Kennedy Krieger Institute, Johns Hopkins School of Medicine, Baltimore, MD,
USA.
(9)Analysis Group, Inc., Boston, MA, USA.
(10)University Hospitals Leuven, Leuven, Belgium.
(11)University of California Davis Health System, Sacramento, CA, USA.
(12)Catholic University, Rome, Italy.
BACKGROUND: Studies 4658-201/202 (201/202) evaluated treatment effects of
eteplirsen over 4 years in patients with Duchenne muscular dystrophy and
confirmed exon-51 amenable genetic mutations. Chart review Study 4658-405 (405)
further followed these patients while receiving eteplirsen during usual clinical
care.
OBJECTIVE: To compare long-term clinical outcomes of eteplirsen-treated patients
from Studies 201/202/405 with those of external controls.
METHODS: Median total follow-up time was approximately 6 years of eteplirsen
treatment. Outcomes included loss of ambulation (LOA) and percent-predicted
forced vital capacity (FVC%p). Time to LOA was compared between
eteplirsen-treated patients and standard of care (SOC) external controls and was
measured from eteplirsen initiation in 201/202 or, in the SOC group, from the
first study visit. Comparisons were conducted using univariate Kaplan-Meier
analyses and log-rank tests, and multivariate Cox proportional hazards models
with regression adjustment for baseline characteristics. Annual change in FVC%p
was compared between eteplirsen-treated patients and natural history study
patients using linear mixed models with repeated measures.
RESULTS: Data were included from all 12 patients in Studies 201/202 and the 10
patients with available data from 405. Median age at LOA was 15.16 years.
Eteplirsen-treated patients experienced a statistically significant longer
median time to LOA by 2.09 years (5.09 vs. 3.00 years, p < 0.01) and
significantly attenuated rates of pulmonary decline vs. natural history patients
(FVC%p change: -3.3 vs. -6.0 percentage points annually, p < 0.0001).
CONCLUSIONS: Study 405 highlights the functional benefits of eteplirsen on
ambulatory and pulmonary function outcomes up to 7 years of follow-up in
comparison to external controls.
DOI: 10.3233/JND-210665
PMCID: PMC8842766
PMID: 34420980 [Indexed for MEDLINE]
Conflict of interest statement: Olga Mitelman, Ashish Dugar, and Sourav Santra
are employees of Sarepta Therapeutics, Inc. and own Sarepta Therapeutics, Inc.
stock. Hoda Z. Abdel-Hamid served on advisory boards for AveXis, Audentes,
Biogen, and Sarepta Therapeutics, Inc. Barry J. Byrne is the co-founder of
Aavanti Bio, Inc. Anne M. Connolly served on advisory boards for Acceleron,
AveXis, Genentech, Edgewise, and Sarepta Therapeutics, Inc., and on DMSB for
Catabasis. Peter Heydemann served on advisory panels for Sarepta Therapeutics,
Inc. and PTC Therapeutics. Crystal Proud served on advisory boards for AveXis,
Biogen, Sarepta Therapeutics, Inc., is a speaker for AveXis, Biogen, has or is
conducting research for AveXis, Astellas, Biogen, Catabasis, CSL Behring, PTC
Therapeutics, Pfizer, Sarepta Therapeutics Inc., and Scholar Rock. Perry B.
Shieh is a consultant for AveXis, Biogen, PTC Therapeutics, and Sarepta
Therapeutics, Inc., and serves on speaker bureaus for Alexion, Biogen, and
Grifols. Kathryn R. Wagner is a consultant for AskBio, Dynacure, PTC
Therapeutics, Roche, and Sarepta Therapeutics, Inc., and serves on the DSMB for
Fibrogen and on a dose escalation committee for Wave Life Sciences. James
Signorovitch is a member of the collaborative Trajectory Analysis Project and is
an employee of Analysis Group, Inc., a consulting firm that received payment
from Sarepta Therapeutics, Inc. to conduct this research. Nathalie Goemans has
served on clinical steering committees and/or as a consultant and received
compensation from Eli Lilly, Italfarmaco SpA, PTC Therapeutics, BioMarin
Pharmaceutical, Sarepta Therapeutics, Inc., Pfizer Inc., Roche, Wave Life
Sciences; has served as site investigator for GlaxoSmithKline, Prosensa,
BioMarin Pharmaceutical, Italfarmaco SpA, Sarepta Therapeutics, Inc., Wave Life
Sciences, Roche, and Eli Lilly. Craig M. McDonald has served as a consultant for
PTC Therapeutics, BioMarin Pharmaceutical, Sarepta Therapeutics, Inc., Eli
Lilly, Pfizer Inc., Santhera Pharmaceuticals, Epirium Bio (formerly Cardero
Therapeutics, Inc.), Catabasis Pharmaceuticals, Capricor Therapeutics, Astellas
Pharma (Mitobridge), Italfarmaco, Edgewise Therapeutics, and FibroGen, Inc.;
serves on external advisory boards related to Duchenne muscular dystrophy for
PTC Therapeutics, Sarepta Therapeutics, Inc., Santhera Pharmaceuticals, Avidity
Biosciences, and Capricor Therapeutics; and reports grants from United States
Department of Education/National Institute on Disability and Rehabilitation
Research, The National Institute on Disability, Independent Living, and
Rehabilitation Research, United States National Institute of Health/National
Institute of Arthritis and Musculoskeletal and Skin Diseases, National
Institutes of Health /National Institute of Neurological Disorders and Stroke,
United States Department of Defense, and Parent Project Muscular Dystrophy US,
during the conduct of the study. Eugenio Mercuri has served on clinical steering
committees and/or as a consultant for Italfarmaco SpA, PTC Therapeutics,
Prosensa, Sarepta Therapeutics, Santhera Pharmaceuticals, and BioMarin
Pharmaceutical; has served as site investigator for GlaxoSmithKline, Prosensa,
BioMarin Pharmaceutical, Italfarmaco SpA, Pfizer Inc., Sarepta Therapeutics,
Inc., Santhera Pharmaceuticals, Roche, and Eli Lilly. Jerry R. Mendell has
received grants from the Parent Project Muscular Dystrophy and has received
personnel fees from Sarepta Therapeutics, Inc. and National Children’s Hospital.
The LNMRC Natural History study has been supported by the Klinisch
Onderzoeksfonds UZ Leuven and the Fonds voor Spierzieke Kinderen.
Coinvestigator: Marleen van den Hauwe (University Hospitals Leuven, Leuven,
Belgium). The Italian DMD Registry was funded by the Fondazione Telethon (GUP
09010 and GUP 07009). Coinvestigators: Pane M, Mazzone ES, Sormani MP, Messina
S, D’Amico A, Vita G, Fanelli L, Berardinelli A, Coratti G, Torrente Y, Frosini
S, Norcia G, Rolle E, Magri F, Palermo C, Rossi F, Donati MA, Sacchini M,
Arnoldi MT, Baranello G, Mongini T, Pini A, Battini R, Pegoraro E, Previtali S,
Bruno C, Politano L, Comi GP, Bertini E, Brogna C. The Cooperative International
Neuromuscular Research Group (CINRG) Duchenne Natural History Study was funded
by the United States Department of Education/National Institute on Disability
and Rehabilitation Research (#H133B031118, #H133B090001); United States
Department of Defense (#W81XWH-12-1-0417); National Institutes of
Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases
(#R01AR061875); Parent Project Muscular Dystrophy. Coinvestigators: Alberto
Dubrovsky (Instituto de Neurosciencias Fundacion Favaloro, Buenos Aires,
Argentina); Andrew Kornberg, Monique Ryan (Royal Children’s Hospital, Melbourne,
Victoria, Australia); Richard Webster (Children’s Hospital at Westmead, Sydney,
New South Wales, Australia); Jean K. Mah (Alberta Children’s Hospital, Calgary,
Alberta, Canada); Hanna Kolski (University of Alberta, Edmonton, Alberta,
Canada); W. Douglas Biggar, Laura C. McAdam (Holland Bloorview Kids Rehab
Hospital, Toronto, Ontario, Canada); S. Chidambaranathan, V. Viswanathan
(Sundaram Medical Foundation and Apollo Children’s Hospital, Chennai, India);
Yoram Nevo (Hadassah Hebrew University Hospital, Jerusalem, Israel); Ksenija
Gorni (University of Pavia and Niguarda Ca’ Granda Hospital, Milan, Italy); Jose
Carlo (University of Puerto Rico, San Juan, Puerto Rico); Mar Tulinius (Queen
Silvia Children’s Hospital, Gothenburg, Sweden); Richard T. Abresch, Erik K.
Henricson, Nanette C. Joyce, Craig M. McDonald (University of California Davis
Health System and School of Medicine, Sacramento, CA, USA); Avital Cnaan, Tina
Duong, Robert Leshner, Lauren P. Morgenroth, Carolina Tesi-Rocha, Mathula
Thangarajh (Children’s National Medical Center, Washington, DC, USA); John W.
Day, Peter Karachunski (University of Minnesota, Minneapolis, MN, USA); Sherilyn
Driscoll, Nancy Kuntz (Mayo Clinic, Rochester, MN, USA); Anne M. Connolly, Alan
Pestronk (Washington University in St Louis, St Louis, MO, USA); Hoda Z.
Abdel-Hamid, Paula R. Clemens (UPMC Children’s Hospital of Pittsburgh,
Pittsburgh, PA, USA); Tulio E. Bertorini (University of Tennessee, Memphis, TN,
USA); Timothy Lotze (Texas Children’s Hospital Houston, TX, USA); Amy D. Harper,
Jean Teasley (Children’s Hospital of Virginia, Richmond, VA, USA). |
http://www.ncbi.nlm.nih.gov/pubmed/33523015 | 1. J Neuromuscul Dis. 2021;8(4):469-479. doi: 10.3233/JND-200548.
Comparison of Long-term Ambulatory Function in Patients with Duchenne Muscular
Dystrophy Treated with Eteplirsen and Matched Natural History Controls.
Mendell JR(1)(2), Khan N(3), Sha N(3), Eliopoulos H(3), McDonald CM(4), Goemans
N(5), Mercuri E(6)(7)(8), Lowes LP(1)(2), Alfano LN(1); Eteplirsen Study Group.
Author information:
(1)Center for Gene Therapy, The Research Institute at Nationwide Children's
Hospital, Columbus, OH, USA.
(2)Department of Pediatrics and Neurology, The Ohio State University, Columbus,
OH, USA.
(3)Sarepta Therapeutics, Inc., Cambridge, MA, USA.
(4)University of California Davis Medical Center, Sacramento, CA, USA.
(5)University Hospitals Leuven, Leuven, Belgium.
(6)Paediatric Neurology, Catholic University, Rome, Italy.
(7)Centro Clinico Nemo, Italy.
(8)Pediatric Neuropsychiatry, Policlinico Gemelli, Rome, Italy.
BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare, X-linked, fatal,
degenerative neuromuscular disease caused by DMD gene mutations. A relationship
between exon skipping and dystrophin production in exon 51-amenable patients
treated with eteplirsen (EXONDYS 51®) is established. Once-weekly eteplirsen
significantly increased dystrophin, with slower decline in ambulatory function
compared to baseline. Long-term treatment with eteplirsen leads to accumulation
of dystrophin over time and observed functional benefits in patients with DMD.
OBJECTIVE: Compare long-term ambulatory function in eteplirsen-treated patients
versus controls.
METHODS: Study 201/202 included 12 eteplirsen-treated patients assessed
twice/year for ambulatory function over 4 years. Ambulatory evaluations
(6-minute walk test [6MWT], loss of ambulation, and North Star Ambulatory
Assessment [NSAA]) were compared with matched controls from Italian Telethon and
Leuven registries.
RESULTS: At Years 3 and 4, eteplirsen-treated patients demonstrated markedly
greater mean 6MWT than controls (difference in change from baseline of 132 m
[95%CI (29, 235), p = 0.015] at Year 3 and 159 m [95%CI (66, 253), p = 0.002] at
Year 4). At Year 4, a significantly greater proportion of eteplirsen-treated
patients were still ambulant versus controls (10/12 vs 3/11; p = 0.020). At Year
3, eteplirsen-treated patients demonstrated milder NSAA decline versus controls
(difference in change from baseline of 2.6, 95%CI [-6, 11]), however, the
difference was not statistically significant; Year 4 control NSAA data were not
available.
CONCLUSION: In this retrospective matched control study, eteplirsen treatment
resulted in attenuation of ambulatory decline over a 4-year observation period,
supporting long-term benefit in patients with DMD.
DOI: 10.3233/JND-200548
PMCID: PMC8385516
PMID: 33523015 [Indexed for MEDLINE]
Conflict of interest statement: This study was sponsored by Sarepta
Therapeutics, Inc. N. Khan, N. Sha, and H. Eliopolous were employees of Sarepta
Therapeutics, Inc. at the time of this study and during manuscript preparation,
and may own stock/option in the company. L. Alfano, J. R. Mendell, C. McDonald,
E. Mercuri, and L. P. Lowes serve as remunerated consultants to Sarepta
Therapeutics, Inc. N. Goemans has nothing to disclose. Employees of Sarepta
Therapeutics, Inc. contributed to the study design, data analysis, and critical
review of the manuscript. The decision to submit resided solely with the
authors. |
http://www.ncbi.nlm.nih.gov/pubmed/35921450 | 1. N Engl J Med. 2022 Aug 4;387(5):408-420. doi: 10.1056/NEJMoa2203395.
Trial of Cinpanemab in Early Parkinson's Disease.
Lang AE(1), Siderowf AD(1), Macklin EA(1), Poewe W(1), Brooks DJ(1), Fernandez
HH(1), Rascol O(1), Giladi N(1), Stocchi F(1), Tanner CM(1), Postuma RB(1),
Simon DK(1), Tolosa E(1), Mollenhauer B(1), Cedarbaum JM(1), Fraser K(1), Xiao
J(1), Evans KC(1), Graham DL(1), Sapir I(1), Inra J(1), Hutchison RM(1), Yang
M(1), Fox T(1), Budd Haeberlein S(1), Dam T(1); SPARK Investigators.
Collaborators: Djamshidian-Tehrani A, Lafontaine AL, Slow E, Corvol JC, Damier
P, Defebvre L, Rascol O, Remy P, Thiriez C, Vacca L, Berg D, Haslinger B,
Kassubek J, Mollenhauer B, Reetz K, Toenges L, Volkmann J, Schlesinger I, Barone
P, Centoze D, Ceravolo R, Colosimo C, Cortelli P, Di Fonzo AB, Iannaccone S,
Tessitore A, Volontè MA, Zappia M, Balaguer Martinez E, Kulisevsky J, López
Lozano JJ, Luquin Piudo R, Domenech MJM, Martinez Castrillo JC, Rivera PM,
Sánchez-Ferro Á, Bandmann O, Foltynie T, Hu M, Pavese N, Silverdale M, Worth P,
Agarwal P, Aldred J, Blindauer K, Chahine L, Ellenbogen A, Espay A, Fang J,
Feigin A, Hauser R, Hinson V, Houghton D, Isaacson S, Kumar R, Leehey M, Litvan
I, Omidvar O, Ondo W, Ostrem J, Pahwa R, Saint-Hilaire MH, Scott B, Shill H,
Shprecher D, Siddiqui M, Simuni T, Stover N, Tagliati M, Metman LV, Videnovic A,
Waters C, Willis A, Wszolek Z, Yang L.
Author information:
(1)From the Edmond J. Safra Program in Parkinson's Disease, University Health
Network, and the University of Toronto, Toronto (A.E.L.), and the Montreal
Neurological Institute, Montreal (R.B.P.); the University of Pennsylvania,
Philadelphia (A.D.S.); the Biostatistics Center, Massachusetts General Hospital
(E.A.M.), Beth Israel Deaconess Medical Center (D.K.S.), and Harvard Medical
School (E.A.M., D.K.S.), Boston, and Biogen, Cambridge (K.F., J.X., K.C.E.,
D.L.G., I.S., J.I., R.M.H., M.Y., S.B.H., T.D.) - all in Massachusetts;
Medizinische Universität Innsbruck, Innsbruck, Austria (W.P.); Newcastle
University, Newcastle upon Tyne (D.J.B.), and Biogen, Maidenhead (T.F.) - both
in the United Kingdom; Aarhus University, Aarhus, Denmark (D.J.B.); the Center
for Neurological Restoration, Cleveland Clinic, and Cleveland Clinic Lerner
College of Medicine - both in Cleveland (H.H.F.); Clinical Investigation Center
1436, the Departments of Clinical Pharmacology and Neurosciences, NS-PARK-French
Clinical Research Infrastructure Network, NeuroToul COEN Center, INSERM,
University Hospital of Toulouse, and the University of Toulouse III - both in
Toulouse, France (O.R.); Tel Aviv Sourasky Medical Center, and the Sackler
School of Medicine and the Sagol School of Neuroscience, Tel Aviv University -
both in Tel Aviv, Israel (N.G.); University San Raffaele and IRCCS San Raffaele
- both in Rome (F.S.); the University of California, San Diego, La Jolla
(C.M.T.), and the San Francisco Veterans Affairs Medical Center, San Francisco
(C.M.T.); the University of Barcelona, Barcelona (E.T.); the Department of
Neurology, University Medical Center Göttingen, Göttingen, and
Paracelsus-Elena-Klinik, Kassel - both in Germany (B.M.); and Coeruleus Clinical
Sciences, Woodbridge, CT (J.M.C.).
BACKGROUND: Aggregated α-synuclein plays an important role in Parkinson's
disease pathogenesis. Cinpanemab, a human-derived monoclonal antibody that binds
to α-synuclein, is being evaluated as a disease-modifying treatment for
Parkinson's disease.
METHODS: In a 52-week, multicenter, double-blind, phase 2 trial, we randomly
assigned, in a 2:1:2:2 ratio, participants with early Parkinson's disease to
receive intravenous infusions of placebo (control) or cinpanemab at a dose of
250 mg, 1250 mg, or 3500 mg every 4 weeks, followed by an active-treatment
dose-blinded extension period for up to 112 weeks. The primary end points were
the changes from baseline in the Movement Disorder Society-sponsored revision of
the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score (range, 0
to 236, with higher scores indicating worse performance) at weeks 52 and 72.
Secondary end points included MDS-UPDRS subscale scores and striatal binding as
assessed on dopamine transporter single-photon-emission computed tomography
(DaT-SPECT).
RESULTS: Of the 357 enrolled participants, 100 were assigned to the control
group, 55 to the 250-mg cinpanemab group, 102 to the 1250-mg group, and 100 to
the 3500-mg group. The trial was stopped after the week 72 interim analysis
owing to lack of efficacy. The change to week 52 in the MDS-UPDRS score was 10.8
points in the control group, 10.5 points in the 250-mg group, 11.3 points in the
1250-mg group, and 10.9 points in the 3500-mg group (adjusted mean difference
vs. control, -0.3 points [95% confidence interval {CI}, -4.9 to 4.3], P = 0.90;
0.5 points [95% CI, -3.3 to 4.3], P = 0.80; and 0.1 point [95% CI, -3.8 to 4.0],
P = 0.97, respectively). The adjusted mean difference at 72 weeks between
participants who received cinpanemab through 72 weeks and the pooled group of
those who started cinpanemab at 52 weeks was -0.9 points (95% CI, -5.6 to 3.8)
for the 250-mg dose, 0.6 points (95% CI, -3.3 to 4.4) for the 1250-mg dose, and
-0.8 points (95% CI, -4.6 to 3.0) for the 3500-mg dose. Results for secondary
end points were similar to those for the primary end points. DaT-SPECT imaging
at week 52 showed no differences between the control group and any cinpanemab
group. The most common adverse events with cinpanemab were headache,
nasopharyngitis, and falls.
CONCLUSIONS: In participants with early Parkinson's disease, the effects of
cinpanemab on clinical measures of disease progression and changes in DaT-SPECT
imaging did not differ from those of placebo over a 52-week period. (Funded by
Biogen; SPARK ClinicalTrials.gov number, NCT03318523.).
Copyright © 2022 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2203395
PMID: 35921450 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/3089897 | 1. Hepatology. 1986 Jul-Aug;6(4):723-8. doi: 10.1002/hep.1840060431.
Drug targeting to the liver with lactosylated albumins: does the glycoprotein
target the drug or is the drug targeting the glycoprotein?
van der Sluijs P, Bootsma HP, Postema B, Moolenaar F, Meijer DK.
The isolated perfused rat liver preparation was employed to study hepatic
disposition of the model drug-carrier conjugate fluorescein-lactosylated albumin
(F-LnHSA) with special reference to the influence of the organic anion
fluorescein on liver cell specificity of the endocytosed neoglycoprotein.
Hepatic clearance of fluoresceinated neoglycoproteins was significantly faster
than clearance of radioiodinated neoglycoproteins. Perfusate clearance of
F-L7HSA and F-L25HSA could not completely be inhibited by a dose of 10 mg
asialoorosomucoid that saturates the hepatocyte receptor-mediated endocytic
process. From these data, we inferred an additional hepatic uptake mechanism,
competing with the Ashwell-receptor-mediated internalization of
galactose-terminated glycoproteins. Clearance experiments with fluoresceinated
125I-human serum albumin in the presence of the polyanionic probe dextran
sulfate revealed a nearly complete (approximately 90%) inhibition of hepatic
uptake, while also a pronounced effect was obtained with colloidal carbon. These
data point to nonparenchymal cell uptake of fluoresceinated protein via
interaction with scavenger receptors. In wash-out studies, it was shown that
about 25% of ligand sequestrated by sinusoidal liver cells escaped degradation
and recycled to the perfusion medium. Our results show that care should be taken
in the use of neoglycoproteins as drug carriers to hepatocytes, since a load of
only 2 to 3 moles fluorescein per mole neoglycoprotein considerably affects
intrahepatic distribution. The relative contribution of nonparenchymal cell
uptake by coupling of acidic drugs to the neoglycoproteins is very probably
inversely related to the number of exposing galactose groups per molecule
neoglycoprotein. This phenomenon of "inversed targeting" could therapeutically
both be useful or detrimental, dependent on the spectrum of cell types that
should be reached by the drug.
DOI: 10.1002/hep.1840060431
PMID: 3089897 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/3610047 | 1. Hepatology. 1987 Jul-Aug;7(4):688-95. doi: 10.1002/hep.1840070412.
Lactosylation of albumin reduces uptake rate of dibromosulfophthalein in
perfused rat liver and dissociation rate from albumin in vitro.
van der Sluijs P, Postema B, Meijer DK.
Two types of models have recently been proposed to describe hepatic uptake
kinetics of protein bound drugs: a model in which dissociation from plasma
protein is rate limiting the process, and a model in which an interaction
between protein and hepatocyte surface is thought to promote dissociation and
uptake of the drug. This study was designed to investigate several aspects of
both models, using lactosylated albumin as a binding protein that can interact
with the Ashwell receptor abundantly present on the hepatocyte.
Dibromosulfophthalein clearance was studied in rat liver in the presence of 150
microM (1%) albumin or 150 microM lactosylated albumin. Initial disappearance
rate from perfusate in the presence of lactosylated albumin indicated a 2-fold
decrease in hepatic uptake rate compared with native albumin. This was confirmed
by compartmental analysis, showing a similar decrease in hepatic uptake rate
constant. Protein binding of dibromosulfophthalein to lactosylated albumin was
only marginally different from normal albumin. Consequently, modification of the
protein retarded uptake of the organic anion at an essentially unchanged unbound
concentration. Fluorescence spectroscopy of lactosylated albumin showed a
blue-shifted tryptophan emission spectrum compared with albumin, indicating
increased hydrophobicity of the neoglycoprotein. We therefore considered a
change in off-and-on rate for binding of dibromosulfophthalein in lactosylated
albumin. Rapid filtration experiments indicated that the dissociation rate
constant of dibromosulfophthalein from lactosylated albumin was half that of
controls. We conclude that the decreased off-rate from lactosylated albumin can
explain the retarding influence on hepatic uptake rate of dibromosulfophthalein.
This observation argues for the concept of dissociation-limited uptake in the
hepatic clearance of the organic anion.
DOI: 10.1002/hep.1840070412
PMID: 3610047 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22919488 | 1. Mol Biol Int. 2012;2012:283974. doi: 10.1155/2012/283974. Epub 2012 Aug 2.
ASGR1 and ASGR2, the Genes that Encode the Asialoglycoprotein Receptor (Ashwell
Receptor), Are Expressed in Peripheral Blood Monocytes and Show Interindividual
Differences in Transcript Profile.
Harris RL(1), van den Berg CW, Bowen DJ.
Author information:
(1)Institute of Molecular and Experimental Medicine, Cardiff University School
of Medicine, Heath Park, Cardiff CF14 4XN, UK.
Background. The asialoglycoprotein receptor (ASGPR) is a hepatic receptor that
mediates removal of potentially hazardous glycoconjugates from blood in health
and disease. The receptor comprises two proteins, asialoglycoprotein receptor 1
and 2 (ASGR1 and ASGR2), encoded by the genes ASGR1 and ASGR2. Design and
Methods. Using reverse transcription amplification (RT-PCR), expression of ASGR1
and ASGR2 was investigated in human peripheral blood monocytes. Results.
Monocytes were found to express ASGR1 and ASGR2 transcripts. Correctly spliced
transcript variants encoding different isoforms of ASGR1 and ASGR2 were present
in monocytes. The profile of transcript variants from both ASGR1 and ASGR2
differed among individuals. Transcript expression levels were compared with the
hepatocyte cell line HepG2 which produces high levels of ASGPR. Monocyte
transcripts were 4 to 6 orders of magnitude less than in HepG2 but nonetheless
readily detectable using standard RT-PCR. The monocyte cell line THP1 gave
similar results to monocytes harvested from peripheral blood, indicating it may
provide a suitable model system for studying ASGPR function in this cell type.
Conclusions. Monocytes transcribe and correctly process transcripts encoding the
constituent proteins of the ASGPR. Monocytes may therefore represent a mobile
pool of the receptor, capable of reaching sites remote from the liver.
DOI: 10.1155/2012/283974
PMCID: PMC3419429
PMID: 22919488 |
http://www.ncbi.nlm.nih.gov/pubmed/20816169 | 1. Methods Enzymol. 2010;479:223-41. doi: 10.1016/S0076-6879(10)79013-3.
The Ashwell-Morell receptor.
Grewal PK(1).
Author information:
(1)The Department of Molecular, Cellular, and Developmental Biology, University
of California Santa Barbara, Santa Barbara, California, USA.
The Ashwell-Morell receptor (AMR) of hepatocytes, originally termed the hepatic
asialoglycoprotein receptor, was the first cellular receptor to be identified
and isolated and the first lectin to be detected in mammals. It is one of the
multiple lectins of the C-type lectin family involved in recognition, binding,
and clearance of asialoglycoproteins. We recently identified endogenous ligands
of the AMR as desialylated prothrombotic components, including platelets and von
Willebrand Factor [Ellies L. G., Ditto D., Levy G. G., Wahrenbrock M., Ginsburg
D., Varki A., Le D. T., and Marth J. D. (2002). Sialyltransferase ST3Gal-IV
operates as a dominant modifier of hemostasis by concealing asialoglycoprotein
receptor ligands. Proc. Natl. Acad. Sci. USA 99: pp. 10042-10047; Grewal, P. K.
Uchiyama, S., Ditto, D., Varki, N., Le, D. T., Nizet, V., Marth, J. D. (2008).
The Ashwell receptor mitigates the lethal coagulopathy of sepsis. Nat. Medicine
14, pp. 648-655]. Among these components, clearance by the liver's AMR is
enhanced by exposure of terminal galactose on the glycan chains. A physiological
role for engaging the AMR in rapid clearance was identified as mitigating
disseminating intravascular coagulopathy in sepsis to promote survival. This
chapter overviews the endogenous ligands of the AMR as components of the
coagulatory system, describes clearance mechanisms of the liver, and details
hematology and coagulation assays used in mouse coagulation studies.
Copyright (c) 2010 Elsevier Inc. All rights reserved.
DOI: 10.1016/S0076-6879(10)79013-3
PMID: 20816169 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18488037 | 1. Nat Med. 2008 Jun;14(6):648-55. doi: 10.1038/nm1760. Epub 2008 May 18.
The Ashwell receptor mitigates the lethal coagulopathy of sepsis.
Grewal PK(1), Uchiyama S, Ditto D, Varki N, Le DT, Nizet V, Marth JD.
Author information:
(1)The Howard Hughes Medical Institute and Department of Cellular and Molecular
Medicine University of California, San Diego, La Jolla, California 92093, USA.
Comment in
Nat Med. 2008 Jun;14(6):606-8. doi: 10.1038/nm0608-606.
J Hepatol. 2009 May;50(5):1060-1. doi: 10.1016/j.jhep.2009.02.008.
The Ashwell receptor, the major lectin of hepatocytes, rapidly clears from blood
circulation glycoproteins bearing glycan ligands that include galactose and
N-acetylgalactosamine. This asialoglycoprotein receptor activity remains a key
factor in the development and administration of glycoprotein pharmaceuticals,
yet a biological purpose of the Ashwell receptor has remained elusive. We have
identified endogenous ligands of the Ashwell receptor as glycoproteins and
regulatory components in blood coagulation and thrombosis that include von
Willebrand factor (vWF) and platelets. The Ashwell receptor normally modulates
vWF homeostasis and is responsible for thrombocytopenia during systemic
Streptococcus pneumoniae infection by eliminating platelets desialylated by the
bacterium's neuraminidase. Hemostatic adaptation by the Ashwell receptor
moderates the onset and severity of disseminated intravascular coagulation
during sepsis and improves the probability of host survival.
DOI: 10.1038/nm1760
PMCID: PMC2853759
PMID: 18488037 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24284176 | 1. Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20218-23. doi:
10.1073/pnas.1313905110. Epub 2013 Nov 27.
Inducing host protection in pneumococcal sepsis by preactivation of the
Ashwell-Morell receptor.
Grewal PK(1), Aziz PV, Uchiyama S, Rubio GR, Lardone RD, Le D, Varki NM, Nizet
V, Marth JD.
Author information:
(1)Center for Nanomedicine, University of California, Santa Barbara, CA 93106.
The endocytic Ashwell-Morell receptor (AMR) of hepatocytes detects pathogen
remodeling of host glycoproteins by neuraminidase in the bloodstream and
mitigates the lethal coagulopathy of sepsis. We have investigated the mechanism
of host protection by the AMR during the onset of sepsis and in response to the
desialylation of blood glycoproteins by the NanA neuraminidase of Streptococcus
pneumoniae. We find that the AMR selects among potential glycoprotein ligands
unmasked by microbial neuraminidase activity in pneumococcal sepsis to eliminate
from blood circulation host factors that contribute to coagulation and
thrombosis. This protection is attributable in large part to the rapid induction
of a moderate thrombocytopenia by the AMR. We further show that neuraminidase
activity in the blood can be manipulated to induce the clearance of AMR ligands
including platelets, thereby preactivating a protective response in pneumococcal
sepsis that moderates the severity of disseminated intravascular coagulation and
enables host survival.
DOI: 10.1073/pnas.1313905110
PMCID: PMC3864324
PMID: 24284176 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/33762439 | 1. Sci Transl Med. 2021 Mar 24;13(586):eabd6737. doi:
10.1126/scitranslmed.abd6737.
Repurposed drugs block toxin-driven platelet clearance by the hepatic
Ashwell-Morell receptor to clear Staphylococcus aureus bacteremia.
Sun J(1)(2)(3), Uchiyama S(1), Olson J(1), Morodomi Y(4), Cornax I(1), Ando
N(1), Kohno Y(1), Kyaw MMT(1), Aguilar B(1), Haste NM(1)(2)(3), Kanaji S(4),
Kanaji T(4), Rose WE(5), Sakoulas G(2), Marth JD(6)(7), Nizet V(8)(2)(3).
Author information:
(1)Biomedical Sciences Graduate Program, UC San Diego, La Jolla, CA 92093, USA.
(2)Department of Pediatrics, UC San Diego, La Jolla, CA 92093, USA.
(3)Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego, La
Jolla, CA 92093, USA.
(4)Department of Molecular Medicine, MERU-Roon Research Center on Vascular
Biology, Scripps Research, La Jolla, CA 92037, USA.
(5)School of Pharmacy, University of Wisconsin, Madison, WI 53705, USA.
(6)Center for Nanomedicine, UC Santa Barbara, Santa Barbara, CA 93106, USA.
(7)Sanford Burnham Prebys Medical Discovery Institute, UC Santa Barbara, Santa
Barbara, CA 93106, USA.
(8)Biomedical Sciences Graduate Program, UC San Diego, La Jolla, CA 92093, USA.
vnizet@health.ucsd.edu.
Staphylococcus aureus (SA) bloodstream infections cause high morbidity and
mortality (20 to 30%) despite modern supportive care. In a human bacteremia
cohort, we found that development of thrombocytopenia was correlated to
increased mortality and increased α-toxin expression by the pathogen.
Platelet-derived antibacterial peptides are important in bloodstream defense
against SA, but α-toxin decreased platelet viability, induced platelet sialidase
to cause desialylation of platelet glycoproteins, and accelerated platelet
clearance by the hepatic Ashwell-Morell receptor (AMR). Ticagrelor (Brilinta), a
commonly prescribed P2Y12 receptor inhibitor used after myocardial infarction,
blocked α-toxin-mediated platelet injury and resulting thrombocytopenia, thereby
providing protection from lethal SA infection in a murine intravenous challenge
model. Genetic deletion or pharmacological inhibition of AMR stabilized platelet
counts and enhanced resistance to SA infection, and the anti-influenza sialidase
inhibitor oseltamivir (Tamiflu) provided similar therapeutic benefit. Thus, a
"toxin-platelet-AMR" regulatory pathway plays a critical role in the
pathogenesis of SA bloodstream infection, and its elucidation provides proof of
concept for repurposing two commonly prescribed drugs as adjunctive therapies to
improve patient outcomes.
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American
Association for the Advancement of Science. No claim to original U.S. Government
Works.
DOI: 10.1126/scitranslmed.abd6737
PMCID: PMC9121309
PMID: 33762439 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: W.E.R. has received
speaking honoraria from Melinta unrelated to the current study. G.S. has
consulted for Allergan, Paratek, and Octapharma unrelated to the current study.
V.N. has consulted for Cellics Therapeutics, Vaxcyte, Clarametyx Biosciences,
SNIPR Biome, Boehringer Ingelheim, and Iogen unrelated to the current study. The
authors do not hold patents related to the current study. |
http://www.ncbi.nlm.nih.gov/pubmed/26185093 | 1. Nat Commun. 2015 Jul 17;6:7737. doi: 10.1038/ncomms8737.
Desialylation is a mechanism of Fc-independent platelet clearance and a
therapeutic target in immune thrombocytopenia.
Li J(1), van der Wal DE(2), Zhu G(3), Xu M(1), Yougbare I(2), Ma L(2), Vadasz
B(1), Carrim N(3), Grozovsky R(4), Ruan M(5), Zhu L(5), Zeng Q(5), Tao L(5),
Zhai ZM(5), Peng J(6), Hou M(6), Leytin V(1), Freedman J(7), Hoffmeister KM(4),
Ni H(8).
Author information:
(1)1] Department of Laboratory Medicine and Pathobiology, University of Toronto,
Toronto, Ontario, Canada M5S 1A8 [2] Toronto Platelet Immunobiology Group,
Toronto, Ontario, Canada M5B 1W8 [3] Department of Laboratory Medicine, Keenan
Research Centre for Biomedical Science of St. Michael's Hospital, Toronto,
Ontario, Canada M5B 1W8.
(2)1] Toronto Platelet Immunobiology Group, Toronto, Ontario, Canada M5B 1W8 [2]
Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science
of St. Michael's Hospital, Toronto, Ontario, Canada M5B 1W8 [3] Canadian Blood
Services, Ottawa, Ontario, Canada K1G 4J5.
(3)1] Toronto Platelet Immunobiology Group, Toronto, Ontario, Canada M5B 1W8 [2]
Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science
of St. Michael's Hospital, Toronto, Ontario, Canada M5B 1W8.
(4)Translational Medicine Division, Brigham and Women's Hospital, Harvard
Medical School, Boston, Massachusetts 02115, USA.
(5)Department of Hematology, Anhui Medical University, Hefei 230032, China.
(6)Department of Hematology, Qilu Hospital, Shandong University, Jinan 250012,
China.
(7)1] Department of Laboratory Medicine and Pathobiology, University of Toronto,
Toronto, Ontario, Canada M5S 1A8 [2] Toronto Platelet Immunobiology Group,
Toronto, Ontario, Canada M5B 1W8 [3] Department of Laboratory Medicine, Keenan
Research Centre for Biomedical Science of St. Michael's Hospital, Toronto,
Ontario, Canada M5B 1W8 [4] Department of Medicine, University of Toronto,
Ontario, Canada M5S 1A8.
(8)1] Department of Laboratory Medicine and Pathobiology, University of Toronto,
Toronto, Ontario, Canada M5S 1A8 [2] Toronto Platelet Immunobiology Group,
Toronto, Ontario, Canada M5B 1W8 [3] Department of Laboratory Medicine, Keenan
Research Centre for Biomedical Science of St. Michael's Hospital, Toronto,
Ontario, Canada M5B 1W8 [4] Canadian Blood Services, Ottawa, Ontario, Canada K1G
4J5 [5] Department of Medicine, University of Toronto, Ontario, Canada M5S 1A8
[6] Department of Physiology, University of Toronto, Ontario, Canada M5S 1A8.
Immune thrombocytopenia (ITP) is a common bleeding disorder caused primarily by
autoantibodies against platelet GPIIbIIIa and/or the GPIb complex. Current
theory suggests that antibody-mediated platelet destruction occurs in the
spleen, via macrophages through Fc-FcγR interactions. However, we and others
have demonstrated that anti-GPIbα (but not GPIIbIIIa)-mediated ITP is often
refractory to therapies targeting FcγR pathways. Here, we generate mouse
anti-mouse monoclonal antibodies (mAbs) that recognize GPIbα and GPIIbIIIa of
different species. Utilizing these unique mAbs and human ITP plasma, we find
that anti-GPIbα, but not anti-GPIIbIIIa antibodies, induces Fc-independent
platelet activation, sialidase neuraminidase-1 translocation and desialylation.
This leads to platelet clearance in the liver via hepatocyte Ashwell-Morell
receptors, which is fundamentally different from the classical Fc-FcγR-dependent
macrophage phagocytosis. Importantly, sialidase inhibitors ameliorate
anti-GPIbα-mediated thrombocytopenia in mice. These findings shed light on
Fc-independent cytopenias, designating desialylation as a potential diagnostic
biomarker and therapeutic target in the treatment of refractory ITP.
DOI: 10.1038/ncomms8737
PMCID: PMC4518313
PMID: 26185093 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8702886 | 1. J Biol Chem. 1996 Aug 30;271(35):21160-6. doi: 10.1074/jbc.271.35.21160.
The major subunit of the asialoglycoprotein receptor is expressed on the
hepatocellular surface in mice lacking the minor receptor subunit.
Braun JR(1), Willnow TE, Ishibashi S, Ashwell G, Herz J.
Author information:
(1)Department of Molecular Genetics, University of Texas Southwestern Medical
Center, Dallas Texas 75235, USA.
The mammalian asialoglycoprotein receptor (ASGPR) is located on the sinusoidal
membrane of hepatocytes where it binds and endocytoses galactose-terminated
glycoproteins (asialoglycoproteins). ASGPR is composed of two highly homologous
subunits, termed hepatic lectin 1 and 2. Despite numerous studies the
contribution of both subunits to biosynthesis and functional activity of ASGPR
in vivo has remained controversial. Mice lacking the murine hepatic lectin
(MHL)-2 subunit are viable and fertile without obvious phenotypic abnormalities.
In the absence of MHL-2, knockout mice express MHL-1 protein at reduced levels.
Here, we examine the intracellular fate and function of this remaining subunit.
The results show that MHL-1 reaches the hepatocellular surface in knockout mice
but is unable to effectively remove any one of three different radiolabeled
ligands within 30 min. A small but detectable residual ligand clearance in
knockout mice at 4 h is apparently not mediated by remaining MHL-1. Serum
concentrations of galactose-terminating glycoproteins are not elevated in these
ASGPR-deficient mice. However, competitive in vitro degradation experiments
suggest that other endogenous ASGPR ligands, the nature of which remain to be
determined, accumulate in serum of knockout animals.
DOI: 10.1074/jbc.271.35.21160
PMID: 8702886 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29233090 | 1. BMC Genomics. 2017 Dec 12;18(1):964. doi: 10.1186/s12864-017-4353-7.
DNA methylation regulates discrimination of enhancers from promoters through a
H3K4me1-H3K4me3 seesaw mechanism.
Sharifi-Zarchi A(1)(2)(3)(4), Gerovska D(5), Adachi K(6), Totonchi M(3), Pezeshk
H(7)(8), Taft RJ(9), Schöler HR(6)(10), Chitsaz H(2), Sadeghi M(8)(11),
Baharvand H(12)(13), Araúzo-Bravo MJ(14)(15)(16).
Author information:
(1)Department of Bioinformatics, Institute of Biochemistry and Biophysics,
University of Tehran, Tehran, Iran.
(2)Computer Science Department, Colorado State University, Fort Collins, CO,
USA.
(3)Department of Stem Cells and Developmental Biology, Cell Science Research
Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran,
Iran.
(4)Department of Computer Engineering, Sharif University of Technology, Tehran,
Iran.
(5)Computational Biology and Systems Biomedicine, Biodonostia Health Research
Institute, 20014, San Sebastián, Spain.
(6)Department of Cell and Developmental Biology, Max Planck Institute for
Molecular Biomedicine, Münster, Germany.
(7)School of Mathematics, Statistics and Computer Science, College of Science,
University of Tehran, Tehran, Iran.
(8)School of Biological Sciences, Institute for Research in Fundamental Sciences
(IPM), Tehran, Iran.
(9)Illumina Inc., San Diego, USA.
(10)Medical Faculty, University of Münster, Münster, Germany.
(11)National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran,
Iran.
(12)Department of Stem Cells and Developmental Biology, Cell Science Research
Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran,
Iran. baharvand@royaninstitute.org.
(13)Department of Developmental Biology, University of Science and Culture,
Tehran, Iran. baharvand@royaninstitute.org.
(14)Computational Biology and Systems Biomedicine, Biodonostia Health Research
Institute, 20014, San Sebastián, Spain. mararabra@yahoo.co.uk.
(15)Computational Biology and Bioinformatics Group, Max Planck Institute for
Molecular Biomedicine, Münster, Germany. mararabra@yahoo.co.uk.
(16)IKERBASQUE, Basque Foundation for Science, 48011, Bilbao, Spain.
mararabra@yahoo.co.uk.
BACKGROUND: DNA methylation at promoters is largely correlated with inhibition
of gene expression. However, the role of DNA methylation at enhancers is not
fully understood, although a crosstalk with chromatin marks is expected.
Actually, there exist contradictory reports about positive and negative
correlations between DNA methylation and H3K4me1, a chromatin hallmark of
enhancers.
RESULTS: We investigated the relationship between DNA methylation and active
chromatin marks through genome-wide correlations, and found anti-correlation
between H3K4me1 and H3K4me3 enrichment at low and intermediate DNA methylation
loci. We hypothesized "seesaw" dynamics between H3K4me1 and H3K4me3 in the low
and intermediate DNA methylation range, in which DNA methylation discriminates
between enhancers and promoters, marked by H3K4me1 and H3K4me3, respectively.
Low methylated regions are H3K4me3 enriched, while those with intermediate DNA
methylation levels are progressively H3K4me1 enriched. Additionally, the
enrichment of H3K27ac, distinguishing active from primed enhancers, follows a
plateau in the lower range of the intermediate DNA methylation level,
corresponding to active enhancers, and decreases linearly in the higher range of
the intermediate DNA methylation. Thus, the decrease of the DNA methylation
switches smoothly the state of the enhancers from a primed to an active state.
We summarize these observations into a rule of thumb of one-out-of-three
methylation marks: "In each genomic region only one out of these three
methylation marks {DNA methylation, H3K4me1, H3K4me3} is high. If it is the DNA
methylation, the region is inactive. If it is H3K4me1, the region is an
enhancer, and if it is H3K4me3, the region is a promoter". To test our model, we
used available genome-wide datasets of H3K4 methyltransferases knockouts. Our
analysis suggests that CXXC proteins, as readers of non-methylated CpGs would
regulate the "seesaw" mechanism that focuses H3K4me3 to unmethylated sites,
while being repulsed from H3K4me1 decorated enhancers and CpG island shores.
CONCLUSIONS: Our results show that DNA methylation discriminates promoters from
enhancers through H3K4me1-H3K4me3 seesaw mechanism, and suggest its possible
function in the inheritance of chromatin marks after cell division. Our analyses
suggest aberrant formation of promoter-like regions and ectopic transcription of
hypomethylated regions of DNA. Such mechanism process can have important
implications in biological process in where it has been reported abnormal DNA
methylation status such as cancer and aging.
DOI: 10.1186/s12864-017-4353-7
PMCID: PMC5727985
PMID: 29233090 [Indexed for MEDLINE]
Conflict of interest statement: ETHICS APPROVAL AND CONSENT TO PARTICIPATE: Not
applicable. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: The
authors declare that they have no competing interests. PUBLISHER’S NOTE:
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations. |
http://www.ncbi.nlm.nih.gov/pubmed/23739122 | 1. J Hum Genet. 2013 Jul;58(7):439-45. doi: 10.1038/jhg.2013.66. Epub 2013 Jun 6.
Histone modifications for human epigenome analysis.
Kimura H(1).
Author information:
(1)Graduate School of Frontier Biosciences, Osaka University, Suita, Japan.
hkimura@fbs.osaka-u.ac.jp
Histones function both positively and negatively in the regulation of gene
expression, mainly governed by post-translational modifications on specific
amino acid residues. Although histone modifications are not necessarily
prerequisite codes, they may still serve as good epigenetic indicators of
chromatin state associated with gene activation or repression. In particular,
six emerging classes of histone H3 modifications are subjected for epigenome
profiling by the International Human Epigenome Consortium. In general,
transcription start sites of actively transcribed genes are marked by
trimethylated H3K4 (H3K4me3) and acetylated H3K27 (H3K27ac), and active
enhancers can be identified by enrichments of both monomethylated H3K4 (H3K4me1)
and H3K27ac. Gene bodies of actively transcribed genes are associated with
trimethylated H3K36 (H3K36me3). Gene repression can be mediated through two
distinct mechanisms involving trimethylated H3K9 (H3K9me3) and trimethylated
H3K27 (H3K27me3). Enrichments of these histone modifications on specific loci,
or in genome wide, in given cells can be analyzed by chromatin
immunoprecipitation (ChIP)-based methods using an antibody directed against the
site-specific modification. When performing ChIP experiments, one should be
careful about the specificity of antibody, as this affects the data
interpretation. If cell samples with preserved histone-DNA contacts are
available, evaluation of histone modifications, in addition to DNA methylaion,
at specific gene loci would be useful for deciphering the epigenome state for
human genetics studies.
DOI: 10.1038/jhg.2013.66
PMID: 23739122 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30858345 | 1. Genome Res. 2019 Apr;29(4):697-709. doi: 10.1101/gr.240093.118. Epub 2019 Mar
11.
Remodeling of epigenome and transcriptome landscapes with aging in mice reveals
widespread induction of inflammatory responses.
Benayoun BA(1), Pollina EA(1), Singh PP(1), Mahmoudi S(1), Harel I(1), Casey
KM(2), Dulken BW(1), Kundaje A(1)(3), Brunet A(1)(4).
Author information:
(1)Department of Genetics, Stanford University School of Medicine, Stanford,
California 94305, USA.
(2)Department of Comparative Medicine, Stanford University School of Medicine,
Stanford, California 94305, USA.
(3)Department of Computer Science, Stanford University, Stanford, California
94305, USA.
(4)Paul F. Glenn Laboratories for the Biology of Aging, Stanford University,
Stanford, California 94305, USA.
Aging is accompanied by the functional decline of tissues. However, a systematic
study of epigenomic and transcriptomic changes across tissues during aging is
missing. Here, we generated chromatin maps and transcriptomes from four tissues
and one cell type from young, middle-aged, and old mice-yielding 143
high-quality data sets. We focused on chromatin marks linked to gene expression
regulation and cell identity: histone H3 trimethylation at lysine 4 (H3K4me3), a
mark enriched at promoters, and histone H3 acetylation at lysine 27 (H3K27ac), a
mark enriched at active enhancers. Epigenomic and transcriptomic landscapes
could easily distinguish between ages, and machine-learning analysis showed that
specific epigenomic states could predict transcriptional changes during aging.
Analysis of data sets from all tissues identified recurrent age-related
chromatin and transcriptional changes in key processes, including the
up-regulation of immune system response pathways such as the interferon
response. The up-regulation of the interferon response pathway with age was
accompanied by increased transcription and chromatin remodeling at specific
endogenous retroviral sequences. Pathways misregulated during mouse aging across
tissues, notably innate immune pathways, were also misregulated with aging in
other vertebrate species-African turquoise killifish, rat, and humans-indicating
common signatures of age across species. To date, our data set represents the
largest multitissue epigenomic and transcriptomic data set for vertebrate aging.
This resource identifies chromatin and transcriptional states that are
characteristic of young tissues, which could be leveraged to restore aspects of
youthful functionality to old tissues.
© 2019 Benayoun et al.; Published by Cold Spring Harbor Laboratory Press.
DOI: 10.1101/gr.240093.118
PMCID: PMC6442391
PMID: 30858345 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21847099 | 1. EMBO J. 2011 Aug 16;30(20):4198-210. doi: 10.1038/emboj.2011.295.
H3K4 tri-methylation provides an epigenetic signature of active enhancers.
Pekowska A(1), Benoukraf T, Zacarias-Cabeza J, Belhocine M, Koch F, Holota H,
Imbert J, Andrau JC, Ferrier P, Spicuglia S.
Author information:
(1)Centre d'Immunologie de Marseille-Luminy, Parc Scientifique de Luminy, Case
906, Marseille, France.
Combinations of post-translational histone modifications shape the chromatin
landscape during cell development in eukaryotes. However, little is known about
the modifications exactly delineating functionally engaged regulatory elements.
For example, although histone H3 lysine 4 mono-methylation (H3K4me1) indicates
the presence of transcriptional gene enhancers, it does not provide clearcut
information about their actual position and stage-specific activity. Histone
marks were, therefore, studied here at genomic loci differentially expressed in
early stages of T-lymphocyte development. The concomitant presence of the three
H3K4 methylation states (H3K4me1/2/3) was found to clearly reflect the activity
of bona fide T-cell gene enhancers. Globally, gain or loss of H3K4me2/3 at
distal genomic regions correlated with, respectively, the induction or the
repression of associated genes during T-cell development. In the Tcrb gene
enhancer, the H3K4me3-to-H3K4me1 ratio decreases with the enhancer's strength.
Lastly, enhancer association of RNA-polymerase II (Pol II) correlated with the
presence of H3K4me3 and Pol II accumulation resulted in local increase of
H3K4me3. Our results suggest the existence of functional links between Pol II
occupancy, H3K4me3 enrichment and enhancer activity.
DOI: 10.1038/emboj.2011.295
PMCID: PMC3199384
PMID: 21847099 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflict
of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/22593555 | 1. Genome Res. 2012 Oct;22(10):2043-53. doi: 10.1101/gr.134833.111. Epub 2012 May
16.
Dynamics of enhancer chromatin signatures mark the transition from pluripotency
to cell specification during embryogenesis.
Bogdanovic O(1), Fernandez-Miñán A, Tena JJ, de la Calle-Mustienes E, Hidalgo C,
van Kruysbergen I, van Heeringen SJ, Veenstra GJ, Gómez-Skarmeta JL.
Author information:
(1)Centro Andaluz de Biología del Desarrollo, CSIC-UPO-JA, 41013 Sevilla, Spain.
The generation of distinctive cell types that form different tissues and organs
requires precise, temporal and spatial control of gene expression. This depends
on specific cis-regulatory elements distributed in the noncoding DNA surrounding
their target genes. Studies performed on mammalian embryonic stem cells and
Drosophila embryos suggest that active enhancers form part of a defined
chromatin landscape marked by histone H3 lysine 4 mono-methylation (H3K4me1) and
histone H3 lysine 27 acetylation (H3K27ac). Nevertheless, little is known about
the dynamics and the potential roles of these marks during vertebrate
embryogenesis. Here, we provide genomic maps of H3K4me1/me3 and H3K27ac at four
developmental time-points of zebrafish embryogenesis and analyze embryonic
enhancer activity. We find that (1) changes in H3K27ac enrichment at enhancers
accompany the shift from pluripotency to tissue-specific gene expression, (2) in
early embryos, the peaks of H3K27ac enrichment are bound by pluripotent factors
such as Nanog, and (3) the degree of evolutionary conservation is higher for
enhancers that become marked by H3K27ac at the end of gastrulation, suggesting
their implication in the establishment of the most conserved (phylotypic)
transcriptome that is known to occur later at the pharyngula stage.
DOI: 10.1101/gr.134833.111
PMCID: PMC3460198
PMID: 22593555 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24038352 | 1. Nucleic Acids Res. 2013 Dec;41(22):10032-43. doi: 10.1093/nar/gkt826. Epub
2013 Sep 12.
Predicting enhancer transcription and activity from chromatin modifications.
Zhu Y(1), Sun L, Chen Z, Whitaker JW, Wang T, Wang W.
Author information:
(1)Department of Chemistry and Biochemistry, UCSD, La Jolla 92093, CA, USA and
Department of Cellular and Molecular Medicine, UCSD, La Jolla, CA 92093-0359,
USA.
Enhancers play a pivotal role in regulating the transcription of distal genes.
Although certain chromatin features, such as the histone acetyltransferase P300
and the histone modification H3K4me1, indicate the presence of enhancers, only a
fraction of enhancers are functionally active. Individual chromatin marks, such
as H3K27ac and H3K27me3, have been identified to distinguish active from
inactive enhancers. However, the systematic identification of the most
informative single modification, or combination thereof, is still lacking.
Furthermore, the discovery of enhancer RNAs (eRNAs) provides an alternative
approach to directly predicting enhancer activity. However, it remains
challenging to link chromatin modifications to eRNA transcription. Herein, we
develop a logistic regression model to unravel the relationship between
chromatin modifications and eRNA synthesis. We perform a systematic assessment
of 24 chromatin modifications in fetal lung fibroblast and demonstrate that a
combination of four modifications is sufficient to accurately predict eRNA
transcription. Furthermore, we compare the ability of eRNAs and H3K27ac to
discriminate enhancer activity. We demonstrate that eRNA is more indicative of
enhancer activity. Finally, we apply our fibroblast trained model to six other
cell-types and successfully predict eRNA synthesis. Thus, we demonstrate the
learned relationships are general and independent of cell-type. We provided a
powerful tool to identify active enhancers and reveal the relationship between
chromatin modifications, eRNA production and enhancer activity.
DOI: 10.1093/nar/gkt826
PMCID: PMC3905895
PMID: 24038352 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21106759 | 1. Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21931-6. doi:
10.1073/pnas.1016071107. Epub 2010 Nov 24.
Histone H3K27ac separates active from poised enhancers and predicts
developmental state.
Creyghton MP(1), Cheng AW, Welstead GG, Kooistra T, Carey BW, Steine EJ, Hanna
J, Lodato MA, Frampton GM, Sharp PA, Boyer LA, Young RA, Jaenisch R.
Author information:
(1)Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Comment in
Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21240-1. doi:
10.1073/pnas.1016297108.
Developmental programs are controlled by transcription factors and chromatin
regulators, which maintain specific gene expression programs through epigenetic
modification of the genome. These regulatory events at enhancers contribute to
the specific gene expression programs that determine cell state and the
potential for differentiation into new cell types. Although enhancer elements
are known to be associated with certain histone modifications and transcription
factors, the relationship of these modifications to gene expression and
developmental state has not been clearly defined. Here we interrogate the
epigenetic landscape of enhancer elements in embryonic stem cells and several
adult tissues in the mouse. We find that histone H3K27ac distinguishes active
enhancers from inactive/poised enhancer elements containing H3K4me1 alone. This
indicates that the amount of actively used enhancers is lower than previously
anticipated. Furthermore, poised enhancer networks provide clues to unrealized
developmental programs. Finally, we show that enhancers are reset during nuclear
reprogramming.
DOI: 10.1073/pnas.1016071107
PMCID: PMC3003124
PMID: 21106759 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/28759003 | 1. Nat Immunol. 2017 Sep;18(9):1035-1045. doi: 10.1038/ni.3812. Epub 2017 Jul 31.
MLL4 prepares the enhancer landscape for Foxp3 induction via chromatin looping.
Placek K(1), Hu G(1), Cui K(1), Zhang D(2), Ding Y(1)(3), Lee JE(4), Jang Y(4),
Wang C(1)(4), Konkel JE(2), Song J(3), Liu C(5), Ge K(4), Chen W(2), Zhao K(1).
Author information:
(1)Systems Biology Center, Division of Intramural Research, NHLBI, NIH,
Bethesda, Maryland, USA.
(2)Mucosal Immunology Section, Division of Intramural Research, NIDCR, NIH,
Bethesda, Maryland, USA.
(3)Department of Animal and Avian Sciences University of Maryland, College Park,
Maryland, USA.
(4)Adipocyte Biology and Gene Regulation Section, Laboratory of Endocrinology
and Receptor Biology, NIDDK, NIH, Bethesda, Maryland, USA.
(5)Transgenic Core, Division of Intramural Research, NHLBI, NIH, Bethesda,
Maryland, USA.
Comment in
Nat Immunol. 2017 Aug 22;18(9):957-958. doi: 10.1038/ni.3811.
MLL4 is an essential subunit of the histone H3 Lys4 (H3K4)-methylation
complexes. We found that MLL4 deficiency compromised the development of
regulatory T cells (Treg cells) and resulted in a substantial decrease in
monomethylated H3K4 (H3K4me1) and chromatin interaction at putative gene
enhancers, a considerable portion of which were not direct targets of MLL4 but
were enhancers that interacted with MLL4-bound sites. The decrease in H3K4me1
and chromatin interaction at the enhancers not bound by MLL4 correlated with
MLL4 binding at distant interacting regions. Deletion of an upstream
MLL4-binding site diminished the abundance of H3K4me1 at the regulatory elements
of the gene encoding the transcription factor Foxp3 that were looped to the
MLL4-binding site and compromised both the thymic differentiation and the
inducible differentiation of Treg cells. We found that MLL4 catalyzed
methylation of H3K4 at distant unbound enhancers via chromatin looping, which
identifies a previously unknown mechanism for regulating the T cell enhancer
landscape and affecting Treg cell differentiation.
DOI: 10.1038/ni.3812
PMCID: PMC5836551
PMID: 28759003 [Indexed for MEDLINE]
Conflict of interest statement: COMPETING FINANCIAL INTEREST The authors declare
no competing financial interests. |
http://www.ncbi.nlm.nih.gov/pubmed/28981749 | 1. Nucleic Acids Res. 2017 Dec 1;45(21):12195-12213. doi: 10.1093/nar/gkx821.
Chromatin proteomics reveals novel combinatorial histone modification signatures
that mark distinct subpopulations of macrophage enhancers.
Soldi M(1), Mari T(1), Nicosia L(1), Musiani D(1), Sigismondo G(1), Cuomo A(1),
Pavesi G(2), Bonaldi T(1).
Author information:
(1)Department of Experimental Oncology, European Institute of Oncology, Milan
20139, Italy.
(2)Department of Biosciences, Milan University, Milan 20133, Italy.
The integrated activity of cis-regulatory elements fine-tunes transcriptional
programs of mammalian cells by recruiting cell type-specific as well as
ubiquitous transcription factors (TFs). Despite their key role in modulating
transcription, enhancers are still poorly characterized at the molecular level,
and their limited DNA sequence conservation in evolution and variable distance
from target genes make their unbiased identification challenging. The
coexistence of high mono-methylation and low tri-methylation levels of lysine 4
of histone H3 is considered a signature of enhancers, but a comprehensive view
of histone modifications associated to enhancers is still lacking. By combining
chromatin immunoprecipitation (ChIP) with mass spectrometry, we investigated
cis-regulatory regions in macrophages to comprehensively identify histone marks
specifically associated with enhancers, and to profile their dynamics after
transcriptional activation elicited by an inflammatory stimulation. The
intersection of the proteomics data with ChIP-seq and RNA-seq analyses revealed
the existence of novel subpopulations of enhancers, marked by specific histone
modification signatures: specifically, H3K4me1/K36me2 marks transcribed
enhancers, while H3K4me1/K36me3 and H3K4me1/K79me2 combinations mark distinct
classes of intronic enhancers. Thus, our MS analysis of functionally distinct
genomic regions revealed the combinatorial code of histone modifications,
highlighting the potential of proteomics in addressing fundamental questions in
epigenetics.
© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gkx821
PMCID: PMC5716071
PMID: 28981749 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/22537144 | 1. BMC Genomics. 2012 Apr 26;13:152. doi: 10.1186/1471-2164-13-152.
Enhancer identification in mouse embryonic stem cells using integrative modeling
of chromatin and genomic features.
Chen CY(1), Morris Q, Mitchell JA.
Author information:
(1)Department of Cell and Systems Biology, University of Toronto, Toronto, ON,
Canada.
BACKGROUND: Epigenetic modifications, transcription factor (TF) availability and
differences in chromatin folding influence how the genome is interpreted by the
transcriptional machinery responsible for gene expression. Enhancers buried in
non-coding regions are found to be associated with significant differences in
histone marks between different cell types. In contrast, gene promoters show
more uniform modifications across cell types. Here we used histone modification
and chromatin-associated protein ChIP-Seq data sets in mouse embryonic stem (ES)
cells as well as genomic features to identify functional enhancer regions. Using
co-bound sites of OCT4, SOX2 and NANOG (co-OSN, validated enhancers) and
co-bound sites of MYC and MYCN (limited enhancer activity) as enhancer positive
and negative training sets, we performed multinomial logistic regression with
LASSO regularization to identify key features.
RESULTS: Cross validations reveal that a combination of p300, H3K4me1, MED12 and
NIPBL features to be top signatures of co-OSN regions. Using a model from 10
signatures, 83% of top 1277 putative 1 kb enhancer regions (probability greater
than or equal to 0.8) overlapped with at least one TF peak from 7 mouse ES cell
ChIP-Seq data sets. These putative enhancers are associated with increased gene
expression of neighbouring genes and significantly enriched in multiple TF bound
loci in agreement with combinatorial models of TF binding. Furthermore, we
identified several motifs of known TFs significantly enriched in putative
enhancer regions compared to random promoter regions and background. Comparison
with an active H3K27ac mark in various cell types confirmed cell
type-specificity of these enhancers.
CONCLUSIONS: The top enhancer signatures we identified (p300, H3K4me1, MED12 and
NIPBL) will allow for the identification of cell type-specific enhancer regions
in diverse cell types.
DOI: 10.1186/1471-2164-13-152
PMCID: PMC3406964
PMID: 22537144 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35314737 | 1. Sci Rep. 2022 Mar 21;12(1):4795. doi: 10.1038/s41598-022-08645-8.
Shear stress switches the association of endothelial enhancers from ETV/ETS to
KLF transcription factor binding sites.
Tsaryk R(1)(2)(3), Yucel N(4), Leonard EV(1)(2)(3), Diaz N(1)(2), Bondareva
O(2)(5)(6), Odenthal-Schnittler M(1)(2)(5)(7), Arany Z(4), Vaquerizas JM(1)(2),
Schnittler H(1)(2)(5)(7), Siekmann AF(8)(9)(10).
Author information:
(1)Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149,
Münster, Germany.
(2)Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of
Münster, Münster, Germany.
(3)Department of Cell and Developmental Biology and Cardiovascular Institute,
Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA,
USA.
(4)Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
(5)Institute of Anatomy and Vascular Biology, Faculty of Medicine, Westfälische
Wilhelms-Universität Münster, Vesaliusweg 2-4, 48149, Münster, Germany.
(6)Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of
the Helmholtz Zentrum München at the University of Leipzig and University
Hospital Leipzig, Philipp-Rosenthal-Str. 27, 04103, Leipzig, Germany.
(7)Institute of Neuropathology, Westfälische Wilhelms-Universität Münster,
Pottkamp 2, 48149, Münster, Germany.
(8)Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149,
Münster, Germany. arndt.siekmann@pennmedicine.upenn.edu.
(9)Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of
Münster, Münster, Germany. arndt.siekmann@pennmedicine.upenn.edu.
(10)Department of Cell and Developmental Biology and Cardiovascular Institute,
Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA,
USA. arndt.siekmann@pennmedicine.upenn.edu.
Endothelial cells (ECs) lining blood vessels are exposed to mechanical forces,
such as shear stress. These forces control many aspects of EC biology, including
vascular tone, cell migration and proliferation. Despite a good understanding of
the genes responding to shear stress, our insight into the transcriptional
regulation of these genes is much more limited. Here, we set out to study
alterations in the chromatin landscape of human umbilical vein endothelial cells
(HUVEC) exposed to laminar shear stress. To do so, we performed ChIP-Seq for
H3K27 acetylation, indicative of active enhancer elements and ATAC-Seq to mark
regions of open chromatin in addition to RNA-Seq on HUVEC exposed to 6 h of
laminar shear stress. Our results show a correlation of gained and lost
enhancers with up and downregulated genes, respectively. DNA motif analysis
revealed an over-representation of KLF transcription factor (TF) binding sites
in gained enhancers, while lost enhancers contained more ETV/ETS motifs. We
validated a subset of flow responsive enhancers using luciferase-based reporter
constructs and CRISPR-Cas9 mediated genome editing. Lastly, we characterized the
shear stress response in ECs of zebrafish embryos using RNA-Seq. Our results lay
the groundwork for the exploration of shear stress responsive elements in
controlling EC biology.
© 2022. The Author(s).
DOI: 10.1038/s41598-022-08645-8
PMCID: PMC8938417
PMID: 35314737 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/34134708 | 1. BMC Med Genomics. 2021 Jun 16;14(1):162. doi: 10.1186/s12920-021-01007-9.
Epigenetic landscapes of intracranial aneurysm risk haplotypes implicate
enhancer function of endothelial cells and fibroblasts in dysregulated gene
expression.
Poppenberg KE(1)(2), Zebraski HR(1)(3), Avasthi N(1)(3), Waqas M(1)(2), Siddiqui
AH(1)(2), Jarvis JN(4), Tutino VM(5)(6)(7)(8)(9).
Author information:
(1)Canon Stroke and Vascular Research Center, University at Buffalo, Clinical
and Translational Research Center, 875 Ellicott Street, Buffalo, NY, 14214, USA.
(2)Department of Neurosurgery, University at Buffalo, Buffalo, NY, USA.
(3)Department of Biomedical Engineering, University at Buffalo, Buffalo, NY,
USA.
(4)Department of Pediatrics, University at Buffalo, Buffalo, NY, USA.
(5)Canon Stroke and Vascular Research Center, University at Buffalo, Clinical
and Translational Research Center, 875 Ellicott Street, Buffalo, NY, 14214, USA.
vincentt@buffalo.edu.
(6)Department of Neurosurgery, University at Buffalo, Buffalo, NY, USA.
vincentt@buffalo.edu.
(7)Department of Biomedical Engineering, University at Buffalo, Buffalo, NY,
USA. vincentt@buffalo.edu.
(8)Department of Pathology and Anatomical Sciences, University at Buffalo,
Buffalo, NY, USA. vincentt@buffalo.edu.
(9)Department of Mechanical and Aerospace Engineering, University at Buffalo,
Buffalo, NY, USA. vincentt@buffalo.edu.
BACKGROUND: Genome-wide association studies have identified many single
nucleotide polymorphisms (SNPs) associated with increased risk for intracranial
aneurysm (IA). However, how such variants affect gene expression within IA is
poorly understood. We used publicly-available ChIP-Seq data to study chromatin
landscapes surrounding risk loci to determine whether IA-associated SNPs affect
functional elements that regulate gene expression in cell types comprising IA
tissue.
METHODS: We mapped 16 significant IA-associated SNPs to linkage disequilibrium
(LD) blocks within human genome. Using ChIP-Seq data, we examined these regions
for presence of H3K4me1, H3K27ac, and H3K9ac histone marks (typically associated
with latent/active enhancers). This analysis was conducted in several cell types
that are present in IA tissue (endothelial cells, smooth muscle cells,
fibroblasts, macrophages, monocytes, neutrophils, T cells, B cells, NK cells).
In cell types with significant histone enrichment, we used HiC data to
investigate topologically associated domains (TADs) encompassing the LD blocks
to identify genes that may be affected by IA-associated variants. Bioinformatics
were performed to determine the biological significance of these genes. Genes
within HiC-defined TADs were also compared to differentially expressed genes
from RNA-seq/microarray studies of IA tissues.
RESULTS: We found that endothelial cells and fibroblasts, rather than smooth
muscle or immune cells, have significant enrichment for enhancer marks on IA
risk haplotypes (p < 0.05). Bioinformatics demonstrated that genes within TADs
subsuming these regions are associated with structural extracellular matrix
components and enzymatic activity. The majority of histone marked TADs (83%
fibroblasts [IMR90], 77% HUVEC) encompassed at least one differentially
expressed gene from IA tissue studies.
CONCLUSIONS: These findings provide evidence that genetic variants associated
with IA risk act on endothelial cells and fibroblasts. There is strong
circumstantial evidence that this may be mediated through altered enhancer
function, as genes in TADs encompassing enhancer marks have also been shown to
be differentially expressed in IA tissue. These genes are largely related to
organization and regulation of the extracellular matrix. This study builds upon
our previous (Poppenberg et al., BMC Med Genomics, 2019) by including a more
diverse set of data from additional cell types and by identifying potential
affected genes (i.e. those in TADs).
DOI: 10.1186/s12920-021-01007-9
PMCID: PMC8210394
PMID: 34134708 [Indexed for MEDLINE]
Conflict of interest statement: KEP, HRZ, NA, MW—None. AHS—Financial
Interest/Investor/Stock Options/Ownership: Amnis Therapeutics, Apama Medi- cal,
BlinkTBI, Inc, Buffalo Technology Partners, Inc., Cardinal Health, Cerebrotech
Medical Systems, Inc, Claret Medical, Cognition Medical, Endostream Medical,
Ltd, Imperative Care, International Medical Distribution Partners, Rebound
Therapeutics Corp., Silk Road Medical, StimMed, Synchron, Three Rivers Medi-
cal, Inc., Viseon Spine, Inc. Consultant/Advisory Board: Amnis Therapeutics,
Boston Scientific, Canon Medical Systems USA, Inc., Cerebrotech Medical Systems,
Inc., Cerenovus, Claret Medical, Corindus, Inc., Endostream Medical, Ltd,
Guidepoint Global Consulting, Imperative Care, Integra, Medtronic, Micro-
Vention, Northwest University—DSMB Chair for HEAT Trial, Penumbra, Rapid
Medical, Rebound Therapeutics Corp., Silk Road Medical, StimMed, Stryker, Three
Rivers Medical, Inc., VasSol, W.L. Gore & Associates. National PI/Steering
Committees: Cerenovus LARGE Trial and ARISE II Trial, Medtronic SWIFT PRIME and
SWIFT DIRECT Trials, MicroVention FRED Trial & CONFIDENCE Study, MUSC POSITIVE
Trial, Penumbra 3D Separator Trial, COMPASS Trial, INVEST Trial. Principal
investigator: Cummings Foundation grant. JNJ—Principal Investigator:
R21-AR071878. VMT—Principal investigator: National Science Foundation Award No.
1746694 and NIH NINDS award R43 NS115314-0. Grant funding from: Brain Aneurysm
Foundation grant, Centers for Advanced Technology grant (through NY Empire State
Development), and Cummings Foundation. Co-founder: Neurovascular Diagnostics,
Inc. |
http://www.ncbi.nlm.nih.gov/pubmed/29255264 | 1. Nat Genet. 2018 Jan;50(1):73-82. doi: 10.1038/s41588-017-0015-6. Epub 2017 Dec
18.
Identification of H3K4me1-associated proteins at mammalian enhancers.
Local A(#)(1)(2), Huang H(#)(1)(3), Albuquerque CP(1), Singh N(1), Lee AY(1),
Wang W(4), Wang C(4), Hsia JE(1), Shiau AK(1), Ge K(5), Corbett KD(1)(6), Wang
D(4), Zhou H(1)(6), Ren B(7)(8)(9).
Author information:
(1)Ludwig Institute for Cancer Research, La Jolla, CA, USA.
(2)Aptose Biosciences, Inc., San Diego, CA, USA.
(3)Biomedical Sciences Graduate Program, University of California, San Diego, La
Jolla, CA, USA.
(4)Skaggs School of Pharmacy and Pharmaceutical Sciences, University of
California, San Diego, La Jolla, CA, USA.
(5)National Institute of Diabetes and Digestive and Kidney Diseases, US National
Institutes of Health, Bethesda, MD, USA.
(6)Department of Cellular and Molecular Medicine, University of California San
Diego School of Medicine, La Jolla, CA, USA.
(7)Ludwig Institute for Cancer Research, La Jolla, CA, USA. biren@ucsd.edu.
(8)Department of Cellular and Molecular Medicine, University of California San
Diego School of Medicine, La Jolla, CA, USA. biren@ucsd.edu.
(9)Center for Epigenomics, Institute of Genomic Medicine, La Jolla, CA, USA.
biren@ucsd.edu.
(#)Contributed equally
Comment in
Nat Genet. 2018 Jan;50(1):4-5. doi: 10.1038/s41588-017-0018-3.
Enhancers act to regulate cell-type-specific gene expression by facilitating the
transcription of target genes. In mammalian cells, active or primed enhancers
are commonly marked by monomethylation of histone H3 at lysine 4 (H3K4me1) in a
cell-type-specific manner. Whether and how this histone modification regulates
enhancer-dependent transcription programs in mammals is unclear. In this study,
we conducted SILAC mass spectrometry experiments with mononucleosomes and
identified multiple H3K4me1-associated proteins, including many involved in
chromatin remodeling. We demonstrate that H3K4me1 augments association of the
chromatin-remodeling complex BAF to enhancers in vivo and that, in vitro,
H3K4me1-marked nucleosomes are more efficiently remodeled by the BAF complex.
Crystal structures of the BAF component BAF45C indicate that monomethylation,
but not trimethylation, is accommodated by BAF45C's H3K4-binding site. Our
results suggest that H3K4me1 has an active role at enhancers by facilitating
binding of the BAF complex and possibly other chromatin regulators.
DOI: 10.1038/s41588-017-0015-6
PMCID: PMC6007000
PMID: 29255264 [Indexed for MEDLINE]
Conflict of interest statement: Competing financial Interests The authors
declare no competing financial interests. |
http://www.ncbi.nlm.nih.gov/pubmed/28916725 | 1. J Biol Chem. 2017 Nov 17;292(46):18937-18950. doi: 10.1074/jbc.M117.793117.
Epub 2017 Sep 15.
Characterization of enhancers and the role of the transcription factor KLF7 in
regulating corneal epithelial differentiation.
Klein RH(1)(2), Hu W(1), Kashgari G(1), Lin Z(1), Nguyen T(1)(2), Doan M(1),
Andersen B(3)(2)(4).
Author information:
(1)From the Departments of Biological Chemistry and.
(2)Institute for Genomics and Bioinformatics, University of California, Irvine,
California 92697.
(3)From the Departments of Biological Chemistry and bogi@uci.edu.
(4)Medicine, Division of Endocrinology, and.
During tissue development, transcription factors bind regulatory DNA regions
called enhancers, often located at great distances from the genes they regulate,
to control gene expression. The enhancer landscape during embryonic stem cell
differentiation has been well characterized. By contrast, little is known about
the shared and unique enhancer regulatory mechanisms in different ectodermally
derived epithelial cells. Here we use ChIP sequencing (ChIP-seq) to identify
domains enriched for the histone marks histone H3 lysine 4 trimethylation,
histone H3 lysine 4 monomethylation, and histone H3 lysine 27 acetylation
(H3K4me3, H3K4me1, and H3K27ac) and define, for the first time, the super
enhancers and typical enhancers active in primary human corneal epithelial
cells. We show that regulatory regions are often shared between cell types of
the ectodermal lineage and that corneal epithelial super enhancers are already
marked as potential regulatory domains in embryonic stem cells. Kruppel-like
factor (KLF) motifs were enriched in corneal epithelial enhancers, consistent
with the important roles of KLF4 and KLF5 in promoting corneal epithelial
differentiation. We now show that the Kruppel family member KLF7 promotes the
corneal progenitor cell state; on many genes, KLF7 antagonized the corneal
differentiation-promoting KLF4. Furthermore, we found that two SNPs linked
previously to corneal diseases, astigmatism, and Stevens-Johnson syndrome fall
within corneal epithelial enhancers and alter their activity by disrupting
transcription factor motifs that overlap these SNPs. Taken together, our work
defines regulatory enhancers in corneal epithelial cells, highlights global
gene-regulatory relationships shared among different epithelial cells,
identifies a role for KLF7 as a KLF4 antagonist in corneal epithelial cell
differentiation, and explains how two SNPs may contribute to corneal diseases.
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
DOI: 10.1074/jbc.M117.793117
PMCID: PMC5704477
PMID: 28916725 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no conflicts
of interest with the contents of this article. The content is solely the
responsibility of the authors and does not necessarily represent the official
views of the National Institutes of Health |
http://www.ncbi.nlm.nih.gov/pubmed/19021773 | 1. FEBS J. 2008 Dec;275(23):5994-6001. doi: 10.1111/j.1742-4658.2008.06728.x.
Enhancer requirement for histone methylation linked with gene activation.
Rentoft M(1), Kim K, Cho Y, Lee CH, Kim A.
Author information:
(1)Department of Molecular Biology, College of Natural Sciences, Pusan National
University, Korea.
Enhancers cause a high level of transcription and activation of chromatin
structure at target genes. Hyperacetylation of histones H3 and H4, a mark of
active chromatin, is established broadly across target loci by enhancers that
function over long distances. In the present study, we studied the role of an
enhancer in methylation of various lysine residues on H3 by comparing a model
gene locus having an active enhancer with one in which the enhancer has been
inactivated within the context of minichromosomes. The intact enhancer affected
histone methylation at K4, K9 and K36 in distinct ways depending on the
methylation level and the location in the locus. All three lysine residues were
highly tri-methylated in the coding region of the gene linked to the active
enhancer but not the inactive enhancer. However di-methylation of K9 and K36 was
not affected by the enhancer. The enhancer region itself was marked by
mono-methylation at K4 and K9, distinguishing it from the methyl marks in the
gene coding region. These results indicate that an enhancer has roles in
establishing active histone methylation patterns linked with gene transcription
rather than removing methylation linked with gene inactivation.
DOI: 10.1111/j.1742-4658.2008.06728.x
PMID: 19021773 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27617035 | 1. Epigenetics Chromatin. 2016 Sep 9;9(1):37. doi: 10.1186/s13072-016-0087-z.
eCollection 2016.
Pax6 associates with H3K4-specific histone methyltransferases Mll1, Mll2, and
Set1a and regulates H3K4 methylation at promoters and enhancers.
Sun J(1), Zhao Y(1), McGreal R(2), Cohen-Tayar Y(3), Rockowitz S(1), Wilczek
C(4), Ashery-Padan R(3), Shechter D(4), Zheng D(5), Cvekl A(2).
Author information:
(1)Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461
USA.
(2)Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461
USA ; Department of Ophthalmology and Visual Sciences, Albert Einstein College
of Medicine, Bronx, NY 10461 USA.
(3)Department of Human Molecular Genetics and Biochemistry, Faculty of Medicine,
Sagol school of Neuroscience, Tel-Aviv University, Tel Aviv, 69978 Israel.
(4)Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY
10461 USA.
(5)Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461
USA ; Department of Neurology, Albert Einstein College of Medicine, Bronx, NY
10461 USA ; Department of Neuroscience, Albert Einstein College of Medicine,
Bronx, NY 10461 USA.
BACKGROUND: Pax6 is a key regulator of the entire cascade of ocular lens
formation through specific binding to promoters and enhancers of batteries of
target genes. The promoters and enhancers communicate with each other through
DNA looping mediated by multiple protein-DNA and protein-protein interactions
and are marked by specific combinations of histone posttranslational
modifications (PTMs). Enhancers are distinguished from bulk chromatin by
specific modifications of core histone H3, including H3K4me1 and H3K27ac, while
promoters show increased H3K4me3 PTM. Previous studies have shown the presence
of Pax6 in as much as 1/8 of lens-specific enhancers but a much smaller fraction
of tissue-specific promoters. Although Pax6 is known to interact with EP300/p300
histone acetyltransferase responsible for generation of H3K27ac, a potential
link between Pax6 and histone H3K4 methylation remains to be established.
RESULTS: Here we show that Pax6 co-purifies with H3K4 methyltransferase activity
in lens cell nuclear extracts. Proteomic studies show that Pax6
immunoprecipitates with Set1a, Mll1, and Mll2 enzymes, and their associated
proteins, i.e., Wdr5, Rbbp5, Ash2l, and Dpy30. ChIP-seq studies using chromatin
prepared from mouse lens and cultured lens cells demonstrate that Pax6-bound
regions are mostly enriched with H3K4me2 and H3K4me1 in enhancers and promoters,
though H3K4me3 marks only Pax6-containing promoters. The shRNA-mediated
knockdown of Pax6 revealed down-regulation of a set of direct target genes,
including Cap2, Farp1, Pax6, Plekha1, Prox1, Tshz2, and Zfp536. Pax6 knockdown
was accompanied by reduced H3K4me1 at enhancers and H3K4me3 at promoters, with
little or no changes of the H3K4me2 modifications. These changes were prominent
in Plekha1, a gene regulated by Pax6 in both lens and retinal pigmented
epithelium.
CONCLUSIONS: Our study supports a general model of Pax6-mediated recruitment of
histone methyltransferases Mll1 and Mll2 to lens chromatin, especially at distal
enhancers. Genome-wide data in lens show that Pax6 binding correlates with
H3K4me2, consistent with the idea that H3K4me2 PTMs correlate with the binding
of transcription factors. Importantly, partial reduction of Pax6 induces
prominent changes in local H3K4me1 and H3K4me3 modification. Together, these
data open the field to mechanistic studies of Pax6, Mll1, Mll2, and H3K4me1/2/3
dynamics at distal enhancers and promoters of developmentally controlled genes.
DOI: 10.1186/s13072-016-0087-z
PMCID: PMC5018195
PMID: 27617035 |
http://www.ncbi.nlm.nih.gov/pubmed/28649883 | 1. Expert Rev Proteomics. 2017 Jul;14(7):617-626. doi:
10.1080/14789450.2017.1345632. Epub 2017 Jun 28.
Middle-down proteomics: a still unexploited resource for chromatin biology.
Sidoli S(1), Garcia BA(1).
Author information:
(1)a Epigenetics Institute, Department of Biochemistry and Biophysics, Perelman
School of Medicine , University of Pennsylvania , Philadelphia , PA , USA.
Analysis of histone post-translational modifications (PTMs) by mass spectrometry
(MS) has become a fundamental tool for the characterization of chromatin
composition and dynamics. Histone PTMs benchmark several biological states of
chromatin, including regions of active enhancers, active/repressed gene
promoters and damaged DNA. These complex regulatory mechanisms are often defined
by combinatorial histone PTMs; for instance, active enhancers are commonly
occupied by both marks H3K4me1 and H3K27ac. The traditional bottom-up MS
strategy identifies and quantifies short (aa 4-20) tryptic peptides, and it is
thus not suitable for the characterization of combinatorial PTMs. Areas covered:
Here, we review the advancement of the middle-down MS strategy applied to
histones, which consists in the analysis of intact histone N-terminal tails (aa
50-60). Middle-down MS has reached sufficient robustness and reliability, and it
is far less technically challenging than PTM quantification on intact histones
(top-down). However, the very few chromatin biology studies applying middle-down
MS resulting from PubMed searches indicate that it is still very scarcely
exploited, potentially due to the apparent high complexity of method and
analysis. Expert commentary: We will discuss the state-of-the-art workflow and
examples of existing studies, aiming to highlight its potential and feasibility
for studies of cell biologists interested in chromatin and epigenetics.
DOI: 10.1080/14789450.2017.1345632
PMCID: PMC5699467
PMID: 28649883 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30110629 | 1. Cell Rep. 2018 Aug 14;24(7):1722-1729. doi: 10.1016/j.celrep.2018.07.041.
Enhancer Activity Requires CBP/P300 Bromodomain-Dependent Histone H3K27
Acetylation.
Raisner R(1), Kharbanda S(2), Jin L(1), Jeng E(3), Chan E(4), Merchant M(4),
Haverty PM(5), Bainer R(5), Cheung T(6), Arnott D(6), Flynn EM(7), Romero FA(8),
Magnuson S(9), Gascoigne KE(10).
Author information:
(1)Department of Discovery Oncology, Genentech, Inc., South San Francisco, CA
94080, USA.
(2)Calico Labs, South San Francisco, CA 94080, USA.
(3)Program in Cancer Biology and Department of Genetics, Stanford University,
Stanford, CA 94305, USA.
(4)Department of Translational Oncology, Genentech, Inc., South San Francisco,
CA 94080, USA.
(5)Department of Bioinformatics, Genentech, Inc., South San Francisco, CA 94080,
USA.
(6)Department of Protein Science, Genentech, Inc., South San Francisco, CA
94080, USA.
(7)Department of Early Discovery Biochemistry, Genentech, Inc., South San
Francisco, CA 94080, USA.
(8)Unity Biotechnology, Brisbane, CA 94005, USA.
(9)Department of Discovery Chemistry, Genentech, Inc., South San Francisco, CA
94080, USA.
(10)Department of Discovery Oncology, Genentech, Inc., South San Francisco, CA
94080, USA. Electronic address: gascoigne.karen@gene.com.
Acetylation of histone H3 at lysine 27 is a well-defined marker of enhancer
activity. However, the functional impact of this modification at enhancers is
poorly understood. Here, we use a chemical genetics approach to acutely block
the function of the cAMP response element binding protein (CREB) binding protein
(CBP)/P300 bromodomain in models of hematological malignancies and describe a
consequent loss of H3K27Ac specifically from enhancers, despite the continued
presence of CBP/P300 at chromatin. Using this approach to dissect the role of
H3K27Ac at enhancers, we identify a critical role for this modification in the
production of enhancer RNAs and transcription of enhancer-regulated gene
networks.
Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.celrep.2018.07.041
PMID: 30110629 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27681438 | 1. Cell Rep. 2016 Sep 27;17(1):289-302. doi: 10.1016/j.celrep.2016.08.083.
Reversible Regulation of Promoter and Enhancer Histone Landscape by DNA
Methylation in Mouse Embryonic Stem Cells.
King AD(1), Huang K(2), Rubbi L(3), Liu S(4), Wang CY(5), Wang Y(4), Pellegrini
M(3), Fan G(6).
Author information:
(1)Department of Human Genetics and Broad Stem Cell Research Center, David
Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
90095, USA; Molecular Biology Interdepartmental Doctoral Program, University of
California Los Angeles, Los Angeles, CA 90095, USA.
(2)Department of Human Genetics and Broad Stem Cell Research Center, David
Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
90095, USA; Division of Oral Biology and Medicine, School of Dentistry,
University of California Los Angeles, Los Angeles, CA 90095, USA.
(3)Department of Molecular, Cell, and Developmental Biology, University of
California Los Angeles, Los Angeles, CA 90095, USA.
(4)Department of Chemistry, University of California Riverside, Riverside, CA
92521, USA.
(5)Division of Oral Biology and Medicine, School of Dentistry, University of
California Los Angeles, Los Angeles, CA 90095, USA.
(6)Department of Human Genetics and Broad Stem Cell Research Center, David
Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA
90095, USA. Electronic address: gfan@mednet.ucla.edu.
DNA methylation is one of a number of modes of epigenetic gene regulation. Here,
we profile the DNA methylome, transcriptome, and global occupancy of histone
modifications (H3K4me1, H3K4me3, H3K27me3, and H3K27ac) in a series of mouse
embryonic stem cells (mESCs) with varying DNA methylation levels to study the
effects of DNA methylation on deposition of histone modifications. We find that
genome-wide DNA demethylation alters occupancy of histone modifications at both
promoters and enhancers. This is reversed upon remethylation by Dnmt expression.
DNA methylation promotes H3K27me3 deposition at bivalent promoters, while
opposing H3K27me3 at silent promoters. DNA methylation also reversibly regulates
H3K27ac and H3K27me3 at previously identified tissue-specific enhancers. These
effects require DNMT catalytic activity. Collectively, our data show that DNA
methylation is essential and instructive for deposition of specific histone
modifications across regulatory regions, which together influences gene
expression patterns in mESCs.
Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.celrep.2016.08.083
PMCID: PMC5507178
PMID: 27681438 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27454738 | 1. Nat Biotechnol. 2016 Sep;34(9):953-61. doi: 10.1038/nbt.3652. Epub 2016 Jul
25.
Co-ChIP enables genome-wide mapping of histone mark co-occurrence at
single-molecule resolution.
Weiner A(1), Lara-Astiaso D(1), Krupalnik V(2), Gafni O(2), David E(1), Winter
DR(1), Hanna JH(2), Amit I(1).
Author information:
(1)The Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
(2)The Department of Molecular Genetics, Weizmann Institute of Science, Rehovot,
Israel.
Histone modifications play an important role in chromatin organization and
transcriptional regulation, but despite the large amount of genome-wide histone
modification data collected in different cells and tissues, little is known
about co-occurrence of modifications on the same nucleosome. Here we present a
genome-wide quantitative method for combinatorial indexed chromatin
immunoprecipitation (co-ChIP) to characterize co-occurrence of histone
modifications on nucleosomes. Using co-ChIP, we study the genome-wide
co-occurrence of 14 chromatin marks (70 pairwise combinations), and find
previously undescribed co-occurrence patterns, including the co-occurrence of
H3K9me1 and H3K27ac in super-enhancers. Finally, we apply co-ChIP to measure the
distribution of the bivalent H3K4me3-H3K27me3 domains in two distinct mouse
embryonic stem cell (mESC) states and in four adult tissues. We observe dynamic
changes in 5,786 regions and discover both loss and de novo gain of bivalency in
key tissue-specific regulatory genes, suggesting a functional role for bivalent
domains during different stages of development. These results show that co-ChIP
can reveal the complex interactions between histone modifications.
DOI: 10.1038/nbt.3652
PMID: 27454738 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29875794 | 1. Front Genet. 2018 Apr 25;9:132. doi: 10.3389/fgene.2018.00132. eCollection
2018.
Chromatin Landscape Distinguishes the Genomic Loci of Hundreds of
Androgen-Receptor-Associated LincRNAs From the Loci of Non-associated LincRNAs.
daSilva LF(1)(2), Beckedorff FC(1)(2), Ayupe AC(1), Amaral MS(1)(2), Mesel V(2),
Videira A(1)(2), Reis EM(1), Setubal JC(1)(3), Verjovski-Almeida S(1)(2).
Author information:
(1)Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo,
São Paulo, Brazil.
(2)Laboratório de Expressão Gênica em Eucariotos, Instituto Butantan, São Paulo,
Brazil.
(3)Biocomplexity Institute of Virginia Tech, Blacksburg, VA, United States.
Cell signaling events triggered by androgen hormone in prostate cells is
dependent on activation of the androgen receptor (AR) transcription factor.
Androgen hormone binding to AR promotes its displacement from the cytoplasm to
the nucleus and AR binding to DNA motifs, thus inducing activatory and
inhibitory transcriptional programs through a complex regulatory mechanism not
yet fully understood. In this work, we performed RNA-seq deep-sequencing of
LNCaP prostate cancer cells and found over 7000 expressed long intergenic
non-coding RNAs (lincRNAs), of which ∼4000 are novel lincRNAs, and 258 lincRNAs
have their expression activated by androgen. Immunoprecipitation of AR, followed
by large-scale sequencing of co-immunoprecipitated RNAs (RIP-Seq) has identified
in the LNCaP cell line a total of 619 lincRNAs that were significantly enriched
(FDR < 10%, DESeq2) in the anti-Androgen Receptor (antiAR) fraction in relation
to the control fraction (non-specific IgG), and we named them
Androgen-Receptor-Associated lincRNAs (ARA-lincRNAs). A genome-wide analysis
showed that protein-coding gene neighbors to ARA-lincRNAs had a significantly
higher androgen-induced change in expression than protein-coding genes
neighboring lincRNAs not associated to AR. To find relevant epigenetic
signatures enriched at the ARA-lincRNAs' transcription start sites (TSSs) we
used a machine learning approach and identified that the ARA-lincRNA genomic
loci in LNCaP cells are significantly enriched with epigenetic marks that are
characteristic of in cis enhancer RNA regulators, and that the H3K27ac mark of
active enhancers is conspicuously enriched at the TSS of ARA-lincRNAs adjacent
to androgen-activated protein-coding genes. In addition, LNCaP topologically
associating domains (TADs) that comprise chromatin regions with ARA-lincRNAs
exhibit transcription factor contents, epigenetic marks and gene transcriptional
activities that are significantly different from TADs not containing
ARA-lincRNAs. This work highlights the possible involvement of hundreds of
lincRNAs working in synergy with the AR on the genome-wide androgen-induced gene
regulatory program in prostate cells.
DOI: 10.3389/fgene.2018.00132
PMCID: PMC5985396
PMID: 29875794 |
http://www.ncbi.nlm.nih.gov/pubmed/33861387 | 1. Drugs. 2021 May;81(7):875-879. doi: 10.1007/s40265-021-01512-2. Epub 2021 Apr
16.
Casimersen: First Approval.
Shirley M(1).
Author information:
(1)Springer Nature, Mairangi Bay, Private Bag 65901, Auckland, 0754, New
Zealand. dru@adis.com.
Casimersen (Amondys 45™) is an antisense oligonucleotide of the
phosphorodiamidate morpholino oligomer subclass developed by Sarepta
Therapeutics for the treatment of Duchenne muscular dystrophy (DMD) in patients
who have a mutation in the DMD gene that is amenable to exon 45 skipping.
Administered by intravenous infusion, casimersen is designed to bind to exon 45
of the DMD gene pre-mRNA, resulting in skipping of this exon during mRNA
processing, intended to allow for production of an internally truncated but
functional dystrophin protein in patients with DMD. Casimersen received its
first approval on 25 February 2021, in the USA, for the treatment of DMD in
patients who have a confirmed mutation of the DMD gene that is amenable to
exon 45 skipping. The approval, granted under the US FDA Accelerated Approval
Program, was based on an observed increase in dystrophin production in skeletal
muscle in patients treated with casimersen. Casimersen is continuing in
phase III development for the treatment of DMD in several other countries
worldwide. This article summarises the milestones in the development of
casimersen leading to this first approval for DMD. As with other approvals under
the Accelerated Approval Program, continued approval for this indication may be
contingent upon verification of a clinical benefit in confirmatory trials.
DOI: 10.1007/s40265-021-01512-2
PMID: 33861387 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32093010 | 1. Diagnostics (Basel). 2020 Feb 19;10(2):114. doi: 10.3390/diagnostics10020114.
A CRISPR Test for Rapidly and Sensitively Detecting Circulating EGFR Mutations.
Tsou JH(1), Leng Q(1), Jiang F(1).
Author information:
(1)Department of Pathology, University of Maryland School of Medicine, 10 S.
Pine St. Baltimore, MD 21201, USA.
The detection of EGFR mutations in circulating cell-free DNA can enable
personalized therapy for cancer. The current techniques for detecting
circulating EGFR mutations are expensive and time-consuming with moderate
sensitivity. Emerging CRISPR is revolutionizing medical diagnostics and showing
a great promise for nucleic acid detection. This study aims to develop
CRISPR-Cas12a as a simple test to sensitively detect circulating EGFR mutations
in plasma. Serially diluted samples of DNA containing heterozygous EGFR
mutations (L858R and T790M) in wild-type genomic DNA are concurrently tested for
the mutations by a CRISPR-Cas12a system and droplet digital PCR (ddPCR). The
CRISPR-Cas12a system can detect both L858R and T790M with a limit of detection
of 0.005% in less than three hours. ddPCR detects the mutations with a limit of
detection of 0.05% for more than five hours. Plasma samples of 28 lung cancer
patients and 20 cancer-free individuals are tested for the EGFR mutations by
CRISPR-Cas12a system and ddPCR. The CRISPR-Cas12a system could detect L858R in
plasma of two lung cancer patients whose tissue biopsies are positive for L858R,
and one plasma sample of three lung cancer patients whose tissue biopsies are
positive for T790M. ddPCR detects L858R in the same two plasm samples, however,
does not detect T790M in any of the plasma samples. This proof of principle
study demonstrates that the CRISPR-Cas12a system could rapidly and sensitively
detect circulating EGFR mutations, and thus, has potential prognostic or
therapeutic implications.
DOI: 10.3390/diagnostics10020114
PMCID: PMC7168902
PMID: 32093010
Conflict of interest statement: The authors declare no conflict of interest. The
funders had no role in the design of the study; in the collection, analyses, or
interpretation of data; in the writing of the manuscript, or in the decision to
publish the results. |
http://www.ncbi.nlm.nih.gov/pubmed/36317783 | 1. N Engl J Med. 2022 Nov 17;387(20):1833-1842. doi: 10.1056/NEJMoa2206966. Epub
2022 Oct 31.
Safety and Efficacy of a Monoclonal Antibody against Malaria in Mali.
Kayentao K(1), Ongoiba A(1), Preston AC(1), Healy SA(1), Doumbo S(1), Doumtabe
D(1), Traore A(1), Traore H(1), Djiguiba A(1), Li S(1), Peterson ME(1), Telscher
S(1), Idris AH(1), Kisalu NK(1), Carlton K(1), Serebryannyy L(1), Narpala S(1),
McDermott AB(1), Gaudinski M(1), Traore S(1), Cisse H(1), Keita M(1), Skinner
J(1), Hu Z(1), Zéguimé A(1), Ouattara A(1), Doucoure M(1), Dolo A(1), Djimdé
A(1), Traore B(1), Seder RA(1), Crompton PD(1); Mali Malaria mAb Trial Team.
Collaborators: Diakite D, Kalossi I, Keita M, Somboro AAP, Sylla M, Traore S,
M'Barakou A, Fofana B, Sacko S, Konate M, Togara A, Traore L, Traore LK, Diarra
D, Diarra M, Kassogue B, Konare B, Konare M, Konare B, Konate CO, Togora HO,
Doumbia F, Konare Y, Coulibaly S, Adams W, France B, Poole CJ, Bajwa K, Buyyani
L, Lange T, Duvenhage M, Kress DR, Namawejje M, Tang P, Tartakovsky M, Whalen C,
Xiao J, Balde A, Buehn M, Cahill K, Francella S, Frary S, Gulati N, Harmon L,
Jankelevich S, Kopka S, Le K, Miller T, Opher V, Simpson S, Teitelbaum M, Young
K, Kayentao K, Ongoiba A, Preston AC, Healy SA, Doumbo S, Doumtabe D, Telscher
S, Idris AH, Kisalu NK, Carlton K, McDermott AB, Gaudinski M, Hu Z, Zéguimé A,
Dolo A, Djimdé A, Traore B, Seder RA, Crompton PD, Traore A, Traore H, Djiguiba
A, Li S, Peterson ME, Serebryannyy L, Narpala S, Traore S, Cisse H, Keita M,
Ouattara A, Doucoure M, Skinner J.
Author information:
(1)From the Malaria Research and Training Center, Mali International Center for
Excellence in Research, University of Sciences, Techniques, and Technologies of
Bamako, Bamako, Mali (K.K., A. Ongoiba, S.D., D.D., A.T., H.T., A. Djiguiba, S.
Traore, H.C., M.K., A.Z., A. Ouattara, M.D., A. Dolo, A. Djimdé, B.T.); and the
Malaria Infection Biology and Immunity Section, Laboratory of Immunogenetics,
Division of Intramural Research (A.C.P., S.A.H., S.L., M.E.P., J.S., P.D.C.),
and the Biostatistics Research Branch, Division of Clinical Research (Z.H.),
National Institute of Allergy and Infectious Diseases (NIAID), National
Institutes of Health (NIH), Rockville, and the Vaccine Research Center, NIAID,
NIH, Bethesda (S. Telscher, A.H.I., N.K.K., K.C., L.S., S.N., A.B.M., M.G.,
R.A.S.) - all in Maryland.
Comment in
N Engl J Med. 2022 Nov 17;387(20):1898-1899. doi: 10.1056/NEJMe2213148.
BACKGROUND: CIS43LS is a monoclonal antibody that was shown to protect against
controlled Plasmodium falciparum infection in a phase 1 clinical trial. Whether
a monoclonal antibody can prevent P. falciparum infection in a region in which
the infection is endemic is unknown.
METHODS: We conducted a phase 2 trial to assess the safety and efficacy of a
single intravenous infusion of CIS43LS against P. falciparum infection in
healthy adults in Mali over a 6-month malaria season. In Part A, safety was
assessed at three escalating dose levels. In Part B, participants were randomly
assigned (in a 1:1:1 ratio) to receive 10 mg of CIS43LS per kilogram of body
weight, 40 mg of CIS43LS per kilogram, or placebo. The primary efficacy end
point, assessed in a time-to-event analysis, was the first P. falciparum
infection detected on blood-smear examination, which was performed at least
every 2 weeks for 24 weeks. At enrollment, all the participants received
artemether-lumefantrine to clear possible P. falciparum infection.
RESULTS: In Part B, 330 adults underwent randomization; 110 were assigned to
each trial group. The risk of moderate headache was 3.3 times as high with 40 mg
of CIS43LS per kilogram as with placebo. P. falciparum infections were detected
on blood-smear examination in 39 participants (35.5%) who received 10 mg of
CIS43LS per kilogram, 20 (18.2%) who received 40 mg of CIS43LS per kilogram, and
86 (78.2%) who received placebo. At 6 months, the efficacy of 40 mg of CIS43LS
per kilogram as compared with placebo was 88.2% (adjusted 95% confidence
interval [CI], 79.3 to 93.3; P<0.001), and the efficacy of 10 mg of CIS43LS per
kilogram as compared with placebo was 75.0% (adjusted 95% CI, 61.0 to 84.0;
P<0.001).
CONCLUSIONS: CIS43LS was protective against P. falciparum infection over a
6-month malaria season in Mali without evident safety concerns. (Funded by the
National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov
number, NCT04329104.).
Copyright © 2022 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2206966
PMCID: PMC9881676
PMID: 36317783 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33332286 | 1. JCI Insight. 2021 Feb 8;6(3):e143958. doi: 10.1172/jci.insight.143958.
Enhancing durability of CIS43 monoclonal antibody by Fc mutation or AAV delivery
for malaria prevention.
Kisalu NK(1), Pereira LD(1), Ernste K(1), Flores-Garcia Y(2), Idris AH(1),
Asokan M(1), Dillon M(1), MacDonald S(3), Shi W(1), Chen X(1), Pegu A(1), Schön
A(4), Zavala F(2), Balazs AB(3), Francica JR(1), Seder RA(1).
Author information:
(1)Vaccine Research Center (VRC), National Institute of Allergy and Infectious
Diseases (NIAID), NIH, Bethesda, Maryland, USA.
(2)Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health,
Baltimore, Maryland, USA.
(3)Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of
Technology and Harvard University, Cambridge, Massachusetts, USA.
(4)Department of Biology, Johns Hopkins University, Baltimore, Maryland, USA.
CIS43 is a potent neutralizing human mAb that targets a highly conserved
"junctional" epitope in the Plasmodium falciparum (Pf) circumsporozoite protein
(PfCSP). Enhancing the durability of CIS43 in vivo will be important for
clinical translation. Here, 2 approaches were used to improve the durability of
CIS43 in vivo while maintaining potent neutralization. First, the Fc domain was
modified with the LS mutations (CIS43LS) to increase CIS43 binding affinity for
the neonatal Fc receptor (FcRn). CIS43LS and CIS43 showed comparable in vivo
protective efficacy. CIS43LS had 9- to 13-fold increased binding affinity for
human (6.2 nM versus 54.2 nM) and rhesus (25.1 nM versus 325.8 nM) FcRn at
endosomal pH 6.0 compared with CIS43. Importantly, the half-life of CIS43LS in
rhesus macaques increased from 22 days to 39 days compared with CIS43. The
second approach for sustaining antibody levels of CIS43 in vivo is through
adeno-associated virus (AAV) expression. Mice administered once with
AAV-expressing CIS43 had sustained antibody levels of approximately 300 μg/mL
and mediated protection against sequential malaria challenges up to 36 weeks.
Based on these data, CIS43LS has advanced to phase I clinical trials, and AAV
delivery provides a potential next-generation approach for malaria prevention.
DOI: 10.1172/jci.insight.143958
PMCID: PMC7934869
PMID: 33332286 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest: NKK, AHI, and RAS have
submitted a patent application (E-038-2017) describing CIS43 and related
mutants. |
http://www.ncbi.nlm.nih.gov/pubmed/34379916 | 1. N Engl J Med. 2021 Aug 26;385(9):803-814. doi: 10.1056/NEJMoa2034031. Epub
2021 Aug 11.
A Monoclonal Antibody for Malaria Prevention.
Gaudinski MR(1), Berkowitz NM(1), Idris AH(1), Coates EE(1), Holman LA(1),
Mendoza F(1), Gordon IJ(1), Plummer SH(1), Trofymenko O(1), Hu Z(1), Campos
Chagas A(1), O'Connell S(1), Basappa M(1), Douek N(1), Narpala SR(1), Barry
CR(1), Widge AT(1), Hicks R(1), Awan SF(1), Wu RL(1), Hickman S(1), Wycuff D(1),
Stein JA(1), Case C(1), Evans BP(1), Carlton K(1), Gall JG(1), Vazquez S(1),
Flach B(1), Chen GL(1), Francica JR(1), Flynn BJ(1), Kisalu NK(1), Capparelli
EV(1), McDermott A(1), Mascola JR(1), Ledgerwood JE(1), Seder RA(1); VRC 612
Study Team.
Collaborators: Starr Hendel C, Beck A, Ola A, Parker K, Casazza J, Novik L,
Costner P, Cunningham J, Saunders J, Whalen W, Wang X, Arthur A, Eschun AM,
Hicks R, Apte P, Trelles Cartagena C, Williams P, Requilman L, Yamshchikov G,
Buettner C, Le L, Pittman I, Taylor S, Nguyen T, Vasilenko O, Telscher S, Blaku
Z, Jeon JE, Tran C, Jones J, Anderson M, Graves C, Andrews C, Larkin B, Zephir
K, Crompton P, Rosing D, Misasi J, Dowler M, Savransky T, Jin-Clark Y, Perazzo
L, Albright G, Amharref N, Atallah K, Banappagari S, Bastani N, Blackstock D,
Boonyaratanakornkit B, Carey E, Charlton A, Chaudhuri R, Caringal AM, Chen M,
Chen P, Cheng W, Gowetski D, Gulla K, Hastings E, Horwitz J, Ivleva V, Kordella
D, Kueltzo LA, Lagler S, Le M, Lee J, Lei P, Li Y, Nagy A, Patel A, Runsewe P,
Shadrick W, Shetty S, Wang H, Webber C, Vejzagic F, Yang YJ, Seder RA, Gaudinski
MR, Ledgerwood JE, Berkowitz NM, Chen GL, Carlton K, Gall JG, Vazquez S, Hickman
S, Wycuff D, Stein JA, Case C, Kisalu NK, Idris AH, Capparelli EV, Hu Z, Evans
BP, Mascola JR, Holman LA, Mendoza F, Gordon IJ, Campos Chagas A, O'Connell S,
Basappa M, Douek N, Narpala SR, Widge AT, Coates EE, Holman LA, Mendoza F,
Plummer SH, Trofymenko O, Awan SF, Wu RL, Flach B, Francica JR, Flynn BJ,
McDermott A.
Author information:
(1)From the Vaccine Research Center (M.R.G., N.M.B., A.H.I., E.E.C., L.A.H.,
F.M., I.J.G., S.H.P., O.T., S.O., M.B., N.D., S.R.N., C.R.B., A.T.W., R.H.,
S.F.A., R.L.W., S.H., D.W., J.A.S., K.C., J.G.G., S.V., B.F., G.L.C., J.R.F.,
B.J.F., N.K.K., A.M., J.R.M., J.E.L., R.A.S.) and the Biostatistics Research
Branch, Division of Clinical Research (Z.H.), National Institute of Allergy and
Infectious Diseases, National Institutes of Health, Bethesda, the U.S. Public
Health Service Commissioned Corps, Rockville (M.R.G.), the Entomology Branch,
Walter Reed Army Institute of Research, Silver Spring (A.C.C., B.P.E.), and the
Vaccine Clinical Materials Program, Leidos Biomedical Research, Frederick
National Laboratory for Cancer Research, Frederick (C.C.) - all in Maryland; and
the School of Medicine and Skaggs School of Pharmacy and Pharmaceutical
Sciences, University of California San Diego, San Diego (E.V.C.).
Comment in
Med. 2021 Nov 12;2(11):1198-1200. doi: 10.1016/j.medj.2021.10.007.
BACKGROUND: Additional interventions are needed to reduce the morbidity and
mortality caused by malaria.
METHODS: We conducted a two-part, phase 1 clinical trial to assess the safety
and pharmacokinetics of CIS43LS, an antimalarial monoclonal antibody with an
extended half-life, and its efficacy against infection with Plasmodium
falciparum. Part A of the trial assessed the safety, initial side-effect
profile, and pharmacokinetics of CIS43LS in healthy adults who had never had
malaria. Participants received CIS43LS subcutaneously or intravenously at one of
three escalating dose levels. A subgroup of participants from Part A continued
to Part B, and some received a second CIS43LS infusion. Additional participants
were enrolled in Part B and received CIS43LS intravenously. To assess the
protective efficacy of CIS43LS, some participants underwent controlled human
malaria infection in which they were exposed to mosquitoes carrying P.
falciparum sporozoites 4 to 36 weeks after administration of CIS43LS.
RESULTS: A total of 25 participants received CIS43LS at a dose of 5 mg per
kilogram of body weight, 20 mg per kilogram, or 40 mg per kilogram, and 4 of the
25 participants received a second dose (20 mg per kilogram regardless of initial
dose). No safety concerns were identified. We observed dose-dependent increases
in CIS43LS serum concentrations, with a half-life of 56 days. None of the 9
participants who received CIS43LS, as compared with 5 of 6 control participants
who did not receive CIS43LS, had parasitemia according to
polymerase-chain-reaction testing through 21 days after controlled human malaria
infection. Two participants who received 40 mg per kilogram of CIS43LS and
underwent controlled human malaria infection approximately 36 weeks later had no
parasitemia, with serum concentrations of CIS43LS of 46 and 57 μg per milliliter
at the time of controlled human malaria infection.
CONCLUSIONS: Among adults who had never had malaria infection or vaccination,
administration of the long-acting monoclonal antibody CIS43LS prevented malaria
after controlled infection. (Funded by the National Institute of Allergy and
Infectious Diseases; VRC 612 ClinicalTrials.gov number, NCT04206332.).
Copyright © 2021 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2034031
PMCID: PMC8579034
PMID: 34379916 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31178713 | 1. Front Synaptic Neurosci. 2019 May 24;11:16. doi: 10.3389/fnsyn.2019.00016.
eCollection 2019.
Optically Induced Calcium-Dependent Gene Activation and Labeling of Active
Neurons Using CaMPARI and Cal-Light.
Ebner C(1)(2), Ledderose J(3), Zolnik TA(2), Dominiak SE(2), Turko P(1)(4),
Papoutsi A(5), Poirazi P(5), Eickholt BJ(3), Vida I(1)(4), Larkum ME(1)(2),
Sachdev RNS(2).
Author information:
(1)NeuroCure Cluster of Excellence, Charité-Universitätsmedizin Berlin, Berlin,
Germany.
(2)Institute for Biology, Humboldt-Universität zu Berlin, Berlin, Germany.
(3)Institute for Biochemistry, Charité-Universitätsmedizin Berlin, Berlin,
Germany.
(4)Institute for Integrative Neuroanatomy, Charité-Universitätsmedizin Berlin,
Berlin, Germany.
(5)Institute of Molecular Biology and Biotechnology, Foundation for Research and
Technology-Hellas, Heraklion, Greece.
The advent of optogenetic methods has made it possible to use endogeneously
produced molecules to image and manipulate cellular, subcellular, and synaptic
activity. It has also led to the development of photoactivatable
calcium-dependent indicators that mark active synapses, neurons, and circuits.
Furthermore, calcium-dependent photoactivation can be used to trigger gene
expression in active neurons. Here we describe two sets of protocols, one using
CaMPARI and a second one using Cal-Light. CaMPARI, a calcium-modulated
photoactivatable ratiometric integrator, enables rapid network-wide, tunable,
all-optical functional circuit mapping. Cal-Light, a photoactivatable calcium
sensor, while slower to respond than CaMPARI, has the capacity to trigger the
expression of genes, including effectors, activators, indicators, or other
constructs. Here we describe the rationale and provide procedures for using
these two calcium-dependent constructs (1) in vitro in dissociated primary
neuronal cell cultures (CaMPARI & Cal-Light); (2) in vitro in acute brain slices
for circuit mapping (CaMPARI); (3) in vivo for triggering photoconversion or
gene expression (CaMPARI & Cal-Light); and finally, (4) for recovering
photoconverted neurons post-fixation with immunocytochemistry (CaMPARI). The
approaches and protocols we describe are examples of the potential uses of both
CaMPARI & Cal-Light. The ability to mark and manipulate neurons that are active
during specific epochs of behavior has a vast unexplored experimental potential.
DOI: 10.3389/fnsyn.2019.00016
PMCID: PMC6542986
PMID: 31178713 |
http://www.ncbi.nlm.nih.gov/pubmed/28650460 | 1. Nat Biotechnol. 2017 Sep;35(9):858-863. doi: 10.1038/nbt.3902. Epub 2017 Jun
26.
A calcium- and light-gated switch to induce gene expression in activated
neurons.
Lee D(1)(2)(3), Hyun JH(1), Jung K(1), Hannan P(1), Kwon HB(1)(4).
Author information:
(1)Max Planck Florida Institute for Neuroscience, Jupiter, Florida, USA.
(2)Department of Anatomy, College of Medicine, Korea University, Seoul, Republic
of Korea.
(3)Department of Biomedical Science, Brain Korea 21 PLUS, College of Medicine,
Korea University, Seoul, Republic of Korea.
(4)Max Planck Institute of Neurobiology, Martinsried, Germany.
Comment in
Nat Chem Biol. 2017 Aug 18;13(9):923. doi: 10.1038/nchembio.2469.
Nat Biotechnol. 2017 Sep 11;35(9):827-828. doi: 10.1038/nbt.3954.
Despite recent advances in optogenetics, it remains challenging to manipulate
gene expression in specific populations of neurons. We present a dual-protein
switch system, Cal-Light, that translates neuronal-activity-mediated calcium
signaling into gene expression in a light-dependent manner. In cultured neurons
and brain slices, we show that Cal-Light drives expression of the reporter EGFP
with high spatiotemporal resolution only in the presence of both blue light and
calcium. Delivery of the Cal-Light components to the motor cortex of mice by
viral vectors labels a subset of excitatory and inhibitory neurons related to
learned lever-pressing behavior. By using Cal-Light to drive expression of the
inhibitory receptor halorhodopsin (eNpHR), which responds to yellow light, we
temporarily inhibit the lever-pressing behavior, confirming that the labeled
neurons mediate the behavior. Thus, Cal-Light enables dissection of neural
circuits underlying complex mammalian behaviors with high spatiotemporal
precision.
DOI: 10.1038/nbt.3902
PMID: 28650460 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32297955 | 1. Nucleic Acids Res. 2020 May 21;48(9):4891-4901. doi: 10.1093/nar/gkaa244.
A non-canonical promoter element drives spurious transcription of horizontally
acquired bacterial genes.
Warman EA(1), Singh SS(1), Gubieda AG(1), Grainger DC(1).
Author information:
(1)Institute of Microbiology and Infection, School of Biosciences, University of
Birmingham, Edgbaston, Birmingham B15 2TT, UK.
RNA polymerases initiate transcription at DNA sequences called promoters. In
bacteria, the best conserved promoter feature is the AT-rich -10 element; a
sequence essential for DNA unwinding. Further elements, and gene regulatory
proteins, are needed to recruit RNA polymerase to the -10 sequence. Hence, -10
elements cannot function in isolation. Many horizontally acquired genes also
have a high AT-content. Consequently, sequences that resemble the -10 element
occur frequently. As a result, foreign genes are predisposed to spurious
transcription. However, it is not clear how RNA polymerase initially recognizes
such sequences. Here, we identify a non-canonical promoter element that plays a
key role. The sequence, itself a short AT-tract, resides 5 base pairs upstream
of otherwise cryptic -10 elements. The AT-tract alters DNA conformation and
enhances contacts between the DNA backbone and RNA polymerase.
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic
Acids Research.
DOI: 10.1093/nar/gkaa244
PMCID: PMC7229825
PMID: 32297955 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/31863129 | 1. J Mol Evol. 2020 Mar;88(2):179-193. doi: 10.1007/s00239-019-09922-3. Epub 2019
Dec 21.
Promoter Length Affects the Initiation of T7 RNA Polymerase In Vitro: New
Insights into Promoter/Polymerase Co-evolution.
Padmanabhan R(1), Sarcar SN(1), Miller DL(2).
Author information:
(1)The Department of Biological Sciences, The University of Texas at Dallas, 800
W Campbell Rd, Richardson, TX, 75080, USA.
(2)The Department of Biological Sciences, The University of Texas at Dallas, 800
W Campbell Rd, Richardson, TX, 75080, USA. dmiller@utdallas.edu.
Polymerases are integral factors of gene expression and are essential for the
maintenance and transmission of genetic information. RNA polymerases (RNAPs)
differ from other polymerases in that they can bind promoter sequences and
initiate transcription de novo and this promoter recognition requires the
presence of specific DNA binding domains in the polymerase. Bacteriophage T7 RNA
polymerase (T7RNAP) is the prototype for single subunit RNA polymerases which
include bacteriophage and mitochondrial RNAPs, and the structure and mechanistic
aspects of transcription by T7 RNAP are well characterized. Here, we describe
experiments to determine whether the prototype T7 RNAP is able to recognize and
initiate at truncated promoters similar to mitochondrial promoters. Using an in
vitro oligonucleotide transcriptional system, we have assayed transcription
initiation activity by T7 RNAP. These assays have not only defined the limits of
conventional de novo initiation on truncated promoters, but have identified
novel activities of initiation of RNA synthesis. We propose that these novel
activities may be vestigial activities surviving from the transition of single
subunit polymerase initiation using primers to de novo initiation using
promoters.
DOI: 10.1007/s00239-019-09922-3
PMID: 31863129 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/18648001 | 1. J Natl Cancer Inst Monogr. 2008;(39):41-3. doi: 10.1093/jncimonographs/lgn004.
How the c-myc promoter works and why it sometimes does not.
Levens D(1).
Author information:
(1)Gene Regulation Section, Laboratory of Pathology, Center for Cancer Research,
National Cancer Institute, Bldg 10, Rm 2N106, Bethesda, MD 20892-1500, USA.
levens@helix.nih.gov
The c-myc promoter is regulated by scores of signals, transcription factors, and
chromatin components. The logic integrating these multiple signals remains
unexplored. Recent evidence suggests that activated MYC expression is regulated
in several phases: 1) conventional transcription factors trigger transcription
by the RNA polymerase II (pol II) paused within the proximal promoter region.
Concurrently (and probably consequently), newly arrived chromatin-remodeling
complexes mobilize a nucleosome masking the far upstream element (FUSE), 1.7-kb
upstream of the P2 start site; 2) binding by FUSE-binding proteins (first FBP3,
then FBP); and 3) FBP-interacting repressor (FIR) binds FUSE and returns
transcription to basal or steady-state levels. The recruitment and release of
the FBPs and FIR is governed by FUSE-DNA conformation, itself controlled by
dynamic supercoils propagated behind pol II. The organization and operation of
the c-myc promoter make it difficult to inactivate, but sensitive to
disturbances (translocations, viral insertions, amplification, and mutation)
that disrupt the fine-tuning seen at its normal chromosomal context.
DOI: 10.1093/jncimonographs/lgn004
PMCID: PMC2683261
PMID: 18648001 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11298753 | 1. Eur J Biochem. 2001 Apr;268(8):2344-50. doi: 10.1046/j.1432-1327.2001.02114.x.
A novel RNA polymerase binding site upstream of the galactose promoter in
Escherichia coli exhibits promoter-like activity.
Sur R(1), Debnath D, Mukhopadhyay J, Parrack P.
Author information:
(1)Department of Biochemistry, Bose Institute, P 1/12, C.I.T. Scheme VIIM,
Calcutta, India.
RNA polymerase is known to bind and utilize the overlapping promoters P1 and P2
in Escherichia coli galactose operon. We have identified an additional specific
site upstream of P2, where RNA polymerase binds in a heparin-resistant manner.
Binding of polymerase to this site, termed P3, occurs simultaneous to its
binding at P1/P2. We have located this P3 site by DNase I footprinting. A 63
base pair region centered around position - 100 with respect to galP1 is
protected by polymerase. Interestingly, a Pribnow box TATAAT is present within
this protected region (-103 to -108). We have shown that transcription occurs
from P3 in vitro. Primer extension analysis provides direct evidence that P3 is
transcribed in vivo. The start site of transcription has been mapped at -96
position relative to galP1. beta-galactosidase assays with different gal
promoter constructs reveal that while P3 alone functions as a weak in vivo
promoter, it has a synergistic effect on transcription from the gal operon,
since deletion of P3 or specifically mutating its -10 region result in a
substantial reduction in the gal promoter activity.
DOI: 10.1046/j.1432-1327.2001.02114.x
PMID: 11298753 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25693126 | 1. Nat Rev Mol Cell Biol. 2015 Mar;16(3):129-43. doi: 10.1038/nrm3952. Epub 2015
Feb 18.
Structural basis of transcription initiation by RNA polymerase II.
Sainsbury S(1), Bernecky C(1), Cramer P(2).
Author information:
(1)1] Max Planck Institute for Biophysical Chemistry, Department of Molecular
Biology, Am Fassberg 11, 37077 Göttingen, Germany. [2].
(2)Max Planck Institute for Biophysical Chemistry, Department of Molecular
Biology, Am Fassberg 11, 37077 Göttingen, Germany.
Transcription of eukaryotic protein-coding genes commences with the assembly of
a conserved initiation complex, which consists of RNA polymerase II (Pol II) and
the general transcription factors, at promoter DNA. After two decades of
research, the structural basis of transcription initiation is emerging. Crystal
structures of many components of the initiation complex have been resolved, and
structural information on Pol II complexes with general transcription factors
has recently been obtained. Although mechanistic details await elucidation,
available data outline how Pol II cooperates with the general transcription
factors to bind to and open promoter DNA, and how Pol II directs RNA synthesis
and escapes from the promoter.
DOI: 10.1038/nrm3952
PMID: 25693126 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24503515 | 1. Curr Opin Struct Biol. 2014 Apr;25:77-85. doi: 10.1016/j.sbi.2014.01.007. Epub
2014 Feb 4.
Role of DNA sequence based structural features of promoters in transcription
initiation and gene expression.
Bansal M(1), Kumar A(2), Yella VR(2).
Author information:
(1)Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012,
India. Electronic address: mb@mbu.iisc.ernet.in.
(2)Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012,
India.
Regulatory information for transcription initiation is present in a stretch of
genomic DNA, called the promoter region that is located upstream of the
transcription start site (TSS) of the gene. The promoter region interacts with
different transcription factors and RNA polymerase to initiate transcription and
contains short stretches of transcription factor binding sites (TFBSs), as well
as structurally unique elements. Recent experimental and computational analyses
of promoter sequences show that they often have non-B-DNA structural motifs, as
well as some conserved structural properties, such as stability, bendability,
nucleosome positioning preference and curvature, across a class of organisms.
Here, we briefly describe these structural features, the differences observed in
various organisms and their possible role in regulation of gene expression.
Copyright © 2014 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.sbi.2014.01.007
PMID: 24503515 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11433282 | 1. Nat Biotechnol. 2001 Jul;19(7):677-9. doi: 10.1038/90296.
Bidirectionalization of polar promoters in plants.
Xie M(1), He Y, Gan S.
Author information:
(1)Plant Physiology/Biochemistry/Molecular Biology Program, Department of
Agronomy and Tobacco and Health Research Institute, University of Kentucky,
Lexington, KY 40546-0236, USA.
A typical eukaryotic promoter consists of a minimal promoter and other upstream
cis elements. The minimal promoter is essentially a TATA box region where RNA
polymerase II, TATA-binding protein (TBP), and TBP-associated factors (TAFs)
bind to initiate transcription, but minimal promoters alone have no
transcriptional activity. The cis elements, to which tissue-specific or
development-specific transcription factors bind, individually or in combination,
determine the spatio-temporal expression pattern of a promoter at the
transcriptional level. The arrangement of upstream cis elements followed by a
minimal promoter sets the polarity of the promoter. Promoters in plants that
have been cloned and widely used for both basic research and biotechnological
application are generally unidirectional, directing only one gene that has been
fused at its 3' end (downstream). It is often necessary to introduce multiple
genes into plants for metabolic engineering and trait stacking. It is also
desirable to minimize or avoid repeated use of a single promoter that may cause
transcriptional gene silencing. Here we describe a strategy to make polar
promoters bidirectional so that one promoter can direct the expression of two
genes, one on each end of the promoter.
DOI: 10.1038/90296
PMID: 11433282 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/6537904 | 1. Cell. 1984 Feb;36(2):357-69. doi: 10.1016/0092-8674(84)90229-0.
A Drosophila RNA polymerase II transcription factor contains a
promoter-region-specific DNA-binding activity.
Parker CS, Topol J.
Drosophila RNA polymerase II requires at least two chromatographically distinct
transcription factors (designated A and B) to initiate transcription accurately
in vitro. We describe the partial purification and concentration of one of these
transcription factors, the B factor. Footprint analysis of the B fraction
demonstrated the presence of a sequence-specific DNA-binding component in the
transcription factor preparation. This component binds specifically to a 65 bp
region of DNA surrounding the start point of transcription of the histone H3,
H4, and actin 5C genes. Included in this binding region is the TATA box, the
start point of transcription, and a portion of the leader region. The pattern of
protection from DNAase I cleavage on the coding strand of the histone H3 gene is
asymmetric with regard to the complementary noncoding strand. Sequence-specific
binding of the B fraction occurs in the apparent absence of RNA polymerase II.
The potential function of the binding component in the initiation of
transcription by RNA polymerase II is discussed.
DOI: 10.1016/0092-8674(84)90229-0
PMID: 6537904 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/2497942 | 1. Can J Microbiol. 1989 Jan;35(1):30-5. doi: 10.1139/m89-005.
An archaebacterial promoter sequence assigned by RNA polymerase binding
experiments.
Thomm M(1), Wich G, Brown JW, Frey G, Sherf BA, Beckler GS.
Author information:
(1)Lehrstuhl für Mikrobiologie, Universität Regensburg, Federal Republic of
Germany.
To identify an archaebacterial promoter sequence, nuclease protection studies
with the purified RNA polymerase of Methanococcus vannielii were performed. The
enzyme binds specifically both at protein-encoding (hisA and methyl CoM
reductase, component C) and tRNA-rRNA genes. The binding region of the RNA
polymerase extends from 30 base pairs (bp) upstream (-30) to 20 bp downstream
(+20) from the in vivo transcription start site. This finding indicates that the
archaebacterial enzyme recognizes promoters without transacting transcription
factors. The DNA segment protected from nuclease digestion by bound RNA
polymerase contains an octanucleotide sequence centered at -25, which is
conserved between the protein-encoding and the stable RNA genes. According to
the specific binding of the enzyme to only DNA-fragments harbouring this motif,
we propose the sequence TTTATATA as the major recognition signal of the
Methanococcus RNA polymerase. Comparison of this motif with published
archaebacterial DNA sequences revealed the presence of homologous sequences at
the same location upstream of 36 genes. We therefore consider the overall
consensus TTTATAATA as a general element of promoters in archaebacteria. In
spite of the specific binding of the enzyme, most preparations of the
Methanococcus vannielii RNA polymerase are unable to initiate transcription at
the correct sites in vitro. Here we present first evidence for the possible
existence of a transcription factor conferring the ability to the enzyme to
initiate and terminate transcription specifically in vitro.
DOI: 10.1139/m89-005
PMID: 2497942 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/3113736 | 1. Cell. 1987 Aug 28;50(5):693-9. doi: 10.1016/0092-8674(87)90327-8.
Eukaryotic RNA polymerase I promoter binding is directed by protein contacts
with transcription initiation factor and is DNA sequence-independent.
Kownin P, Bateman E, Paule MR.
RNA polymerase I binding to the eukaryotic ribosomal RNA gene
promoter-transcription initiation factor (TIF) complex was examined by in vitro
transcription and footprinting of a series of spacer mutants. Polymerase binds
efficiently to the TIF-promoter complex independently of the DNA sequence in the
polymerase interaction region and initiates transcription a fixed distance
downstream of the TIF binding site on AT-rich templates.
Methidiumpropyl-EDTA.FE(II) footprinting confirms minimal contacts between
polymerase and DNA. We infer that polymerase is directed to the promoter by a
DNA sequence-independent mechanism, solely by protein-protein contacts with TIF.
An initiation step subsequent to binding requires special sequence
characteristics in the transcription start site region.
DOI: 10.1016/0092-8674(87)90327-8
PMID: 3113736 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/3309340 | 1. J Mol Biol. 1987 Jun 5;195(3):745-8. doi: 10.1016/0022-2836(87)90194-x.
Binding of Escherichia coli RNA polymerase to a promoter carrying mutations that
stop transcription initiation.
Johnston F(1), Ponnambalam S, Busby S.
Author information:
(1)University of Birmingham, Department of Biochemistry, England.
The gal P2 promoter can be inactivated by point mutations located in the -10
hexamer sequence or immediately upstream from it. Mutations at either site
reduce expression in vivo and prevent the formation, in vitro, of tight
complexes with RNA polymerase that give a strong footprint and can initiate
transcription. However, with a mutation upstream from the -10 region, RNA
polymerase could still make a specific contact with gal promoter DNA as judged
by interference with cleavage by restriction enzyme SfaNI at a site within the
promoter. In contrast, with a mutation in the -10 hexamer sequence, RNA
polymerase could not make this contact and does not interfere with restriction
by SfaNI.
DOI: 10.1016/0022-2836(87)90194-x
PMID: 3309340 [Indexed for MEDLINE] |