AAV5–Factor VIII Gene Transfer in Severe Hemophilia A
Open accessAbstract
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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Both FVIII-SQ and FIX-R338L demonstrate variable activity measurements in OSA versus chromogenic assay that are reproducible across trials.
“both transgene products, FVIII-SQ and FIX-R338L, demonstrate variable activity measurements in OSA versus chromogenic assay (CSA) determinants of factor activity that are reproducible across trials.144,145,149,152”
From Current clinical applications of in vivo gene therapy with AAVs (2021) · cites this paper as [149]
Multiple HA and HB trials have demonstrated ≥10-fold variability in FVIII:C/FIX:C with the same vector and dose.
“multiple HA and HB trials have demonstrated ≥10-fold variability in FVIII:C/FIX:C with the same vector and dose (Harrington et al., 2020, WFH Virtual Summit, conference).145,149,150,153”
From Current clinical applications of in vivo gene therapy with AAVs (2021) · cites this paper as [149]
The relationship between resolution of transaminitis by corticosteroids and T-cell response is not always clear, as observed in a hemophilia A trial.
“Corticosteroids are the most commonly used agents to resolve transaminitis, however, its relationship with resolution by corticosteroids and T-cell response are not always clear as observed in a hemophilia A trial (28, 105).”
From Immunomodulation in Administration of RAAV: Preclinical and Clinical Adjuvant Pharmacotherapies (2021) · cites this paper as [28]
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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
- 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
- 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 · 2016: 1
- 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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