Cited by 694Hemophilia Treatment and ResearchVirus-based gene therapy researchPlatelet Disorders and Treatments

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AAV5–Factor VIII Gene Transfer in Severe Hemophilia A

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Rangarajan, Savita, Walsh, Liron, Lester, Will, Perry, David, Madan, Bella, Laffan, Michael, Yu, Hua, Vettermann, Christian, Pierce, Glenn F., Wong, Wing Y., Pasi, K. John·2017·New England Journal of Medicine

DOI 10.1056/nejmoa1708483

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Abstract

BACKGROUND: Patients with hemophilia A rely on exogenous factor VIII to prevent bleeding in joints, soft tissue, and the central nervous system. Although successful gene transfer has been reported in patients with hemophilia B, the large size of the factor VIII coding region has precluded improved outcomes with gene therapy in patients with hemophilia A. METHODS: We infused a single intravenous dose of a codon-optimized adeno-associated virus serotype 5 (AAV5) vector encoding a B-domain-deleted human factor VIII (AAV5-hFVIII-SQ) in nine men with severe hemophilia A. Participants were enrolled sequentially into one of three dose cohorts (low dose [one participant], intermediate dose [one participant], and high dose [seven participants]) and were followed through 52 weeks. RESULTS: Factor VIII activity levels remained at 3 IU or less per deciliter in the recipients of the low or intermediate dose. In the high-dose cohort, the factor VIII activity level was more than 5 IU per deciliter between weeks 2 and 9 after gene transfer in all seven participants, and the level in six participants increased to a normal value (>50 IU per deciliter) that was maintained at 1 year after receipt of the dose. In the high-dose cohort, the median annualized bleeding rate among participants who had previously received prophylactic therapy decreased from 16 events before the study to 1 event after gene transfer, and factor VIII use for participant-reported bleeding ceased in all the participants in this cohort by week 22. The primary adverse event was an elevation in the serum alanine aminotransferase level to 1.5 times the upper limit of the normal range or less. Progression of preexisting chronic arthropathy in one participant was the only serious adverse event. No neutralizing antibodies to factor VIII were detected. CONCLUSIONS: The infusion of AAV5-hFVIII-SQ was associated with the sustained normalization of factor VIII activity level over a period of 1 year in six of seven participants who received a high dose, with stabilization of hemostasis and a profound reduction in factor VIII use in all seven participants. In this small study, no safety events were noted, but no safety conclusions can be drawn. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov number, NCT02576795 ; EudraCT number, 2014-003880-38 .).

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Authors: Rangarajan, S., Walsh, L., Lester, W., Perry, D., Madan, B., Laffan, M., Yu, H., Vettermann, C., Pierce, G. F., Wong, W. Y., & Pasi, K. J.
Affiliations: University Hospitals Birmingham NHS Foundation Trust (GB)
ORCID: Rangarajan, Savita
Lester, Will
Madan, Bella
Laffan, Michael
Yu, Hua
Vettermann, Christian
Pierce, Glenn F.
Venue: New England Journal of Medicine
Publisher: Massachusetts Medical Society
Published: 2017-12-28
Volume: 377
Issue: 26
Pages: 2519-2530
ISSN: 0028-4793 (ISSN-L)
1533-4406
DOI: 10.1056/nejmoa1708483
OpenAlex: W2775538622
Cited by: 694
References: 29
Citations by year: 2026: 33 · 2025: 59 · 2024: 65 · 2023: 57 · 2022: 95 · 2021: 81 · 2020: 112 · 2019: 90 · 2018: 95 · 2017: 5
FWCI: 63.65
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: New England Journal of Medicine (publishedVersion)
PubMed (publishedVersion)
ePrints Soton (University of Southampton) (submittedVersion)
Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
Spiral (Imperial College London) (submittedVersion)
Funders: BioMarin Pharmaceutical
University Hospitals Birmingham NHS Foundation Trust
National Institute for Health and Care Research
University of Cambridge
Imperial College London
Imperial College Healthcare NHS Trust
Barts Health NHS Trust
Topics: Health Sciences › Medicine › Hematology › Hemophilia Treatment and Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
Keywords: hemophilia A, gene therapy, factor VIII, B-domain-deleted factor VIII, codon optimization, annualized bleeding rate, factor VIII activity, dose escalation, alanine aminotransferase elevation, chronic arthropathy, neutralizing antibodies
MeSH terms: Dependovirus, Adult, Antibodies, Viral, DNA, Viral, Factor VIII, Genetic Vectors, Hemophilia A, Hemorrhage, Humans, Infusions, Intravenous, Male, Genetic Therapy, Virus Shedding, Young Adult

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AAV5–Factor VIII Gene Transfer in Severe Hemophilia A

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