Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant
Open accessAbstract
BACKGROUND: The prevention of bleeding with adequately sustained levels of clotting factor, after a single therapeutic intervention and without the need for further medical intervention, represents an important goal in the treatment of hemophilia. METHODS: vector genomes per kilogram of body weight in 10 men with hemophilia B who had factor IX coagulant activity of 2% or less of the normal value. Laboratory values, bleeding frequency, and consumption of factor IX concentrate were prospectively evaluated after vector infusion and were compared with baseline values. RESULTS: No serious adverse events occurred during or after vector infusion. Vector-derived factor IX coagulant activity was sustained in all the participants, with a mean (±SD) steady-state factor IX coagulant activity of 33.7±18.5% (range, 14 to 81). On cumulative follow-up of 492 weeks among all the participants (range of follow-up in individual participants, 28 to 78 weeks), the annualized bleeding rate was significantly reduced (mean rate, 11.1 events per year [range, 0 to 48] before vector administration vs. 0.4 events per year [range, 0 to 4] after administration; P=0.02), as was factor use (mean dose, 2908 IU per kilogram [range, 0 to 8090] before vector administration vs. 49.3 IU per kilogram [range, 0 to 376] after administration; P=0.004). A total of 8 of 10 participants did not use factor, and 9 of 10 did not have bleeds after vector administration. An asymptomatic increase in liver-enzyme levels developed in 2 participants and resolved with short-term prednisone treatment. One participant, who had substantial, advanced arthropathy at baseline, administered factor for bleeding but overall used 91% less factor than before vector infusion. CONCLUSIONS: We found sustained therapeutic expression of factor IX coagulant activity after gene transfer in 10 participants with hemophilia who received the same vector dose. Transgene-derived factor IX coagulant activity enabled the termination of baseline prophylaxis and the near elimination of bleeding and factor use. (Funded by Spark Therapeutics and Pfizer; ClinicalTrials.gov number, NCT02484092 .).
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The capsid-specific immune response is dose-dependent and administration of low vector doses of AAV are more likely to induce mild inflammation that is manageable by steroids.
“Further studies confirmed that the capsid-specific immune response is dose-dependent and administration of low vector doses of AAV are more likely to induce mild inflammation that is manageable by steroids [86–88].”
From Immunogenicity of Recombinant Adeno-Associated Virus (AAV) Vectors for Gene Transfer (2023) · cites this paper as [88]
A single FIX-R338L trial reported thrombosis in a subject who achieved FIX:C >200% of normal by one-stage assay, with multiple contributing prothrombotic comorbidities including obesity, kidney failure, and recent cessation of a direct-Xa oral anticoagulant.
“a single FIX-R338L trial reported thrombosis in a subject who achieved FIX:C > 200% of normal (by one-stage assay [OSA]) with potentially multiple contributing prothrombotic comorbidities, including, obesity, kidney failure, and recent cessation of a direct-Xa oral anticoagulant145”
From Current clinical applications of in vivo gene therapy with AAVs (2021) · cites this paper as [145]
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 [145]
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 [145]
CCS are used short-term in conjunction with systemically delivered gene therapies to negate transaminitis and associated CTL-induced injury transgene loss.
“CCS are used short-term in conjunction with systemically delivered gene therapies to negate transaminitis and associated CTL-induced injury transgene loss (30, 65), and reduce T-cell infiltrates in muscular fibers in non-human primates (NHP) (33).”
From Immunomodulation in Administration of RAAV: Preclinical and Clinical Adjuvant Pharmacotherapies (2021) · cites this paper as [30]
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Self-citationComplement Activation by Adeno-Associated Virus-Neutralizing Antibody Complexes
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- Authors
- George, L. A., Sullivan, S. K., Giermasz, A., Rasko, J. E. J., Samelson-Jones, B. J., Ducore, J., Cuker, A., Sullivan, L. M., Majumdar, S., Teitel, J., McGuinn, C. E., Ragni, M. V., Luk, A. Y., Hui, D., Wright, J. F., Chen, Y., Liu, Y., Wachtel, K., Winters, A., Tiefenbacher, S., Arruda, V. R., van der Loo, J. C. M., Zelenaia, O., Takefman, D., Carr, M. E., Couto, L. B., Anguela, X. M., & High, K. A.
- Affiliations
- The University of Sydney (AU)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2017-12-07
- Volume
- 377
- Issue
- 23
- Pages
- 2215-2227
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC6029626
- OpenAlex
- W2773253161
- Cited by
- 762
- References
- 32
- Citations by year
- 2026: 40 · 2025: 76 · 2024: 81 · 2023: 69 · 2022: 87 · 2021: 94 · 2020: 105 · 2019: 98 · 2018: 98 · 2017: 7 · 2016: 3 · 2015: 1 · 2013: 1
- FWCI
- 64.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL064190, T32HL007439, T32HL007150)
- 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 B, gene therapy, factor IX, adeno-associated virus vectors, annualized bleeding rate, transgene expression, elevated liver enzymes
- MeSH terms
- Dependovirus, Adolescent, Adult, Hemophilia B, Factor IX, Genetic Vectors, Hemorrhage, Humans, Male, Middle Aged, Genetic Therapy, Transgenes, Young Adult
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