Long-Term Safety and Efficacy of Factor IX Gene Therapy in Hemophilia B
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BACKGROUND: In patients with severe hemophilia B, gene therapy that is mediated by a novel self-complementary adeno-associated virus serotype 8 (AAV8) vector has been shown to raise factor IX levels for periods of up to 16 months. We wanted to determine the durability of transgene expression, the vector dose-response relationship, and the level of persistent or late toxicity. METHODS: We evaluated the stability of transgene expression and long-term safety in 10 patients with severe hemophilia B: 6 patients who had been enrolled in an initial phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose, and 4 additional patients who received the high dose (2×10(12) vector genomes per kilogram of body weight). The patients subsequently underwent extensive clinical and laboratory monitoring. RESULTS: A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating factor IX to a level that was 1 to 6% of the normal value over a median period of 3.2 years, with observation ongoing. In the high-dose group, a consistent increase in the factor IX level to a mean (±SD) of 5.1±1.7% was observed in all 6 patients, which resulted in a reduction of more than 90% in both bleeding episodes and the use of prophylactic factor IX concentrate. A transient increase in the mean alanine aminotransferase level to 86 IU per liter (range, 36 to 202) occurred between week 7 and week 10 in 4 of the 6 patients in the high-dose group but resolved over a median of 5 days (range, 2 to 35) after prednisolone treatment. CONCLUSIONS: In 10 patients with severe hemophilia B, the infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical improvement. With a follow-up period of up to 3 years, no late toxic effects from the therapy were reported. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00979238.).
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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 [87]
Initial clinical studies of AAV-based gene transfer targeting liver correlated AAV-specific cytotoxic T lymphocyte activation with transaminitis and loss of transgene expression.
“The initial clinical studies of AAV-based gene transfer targeting liver correlated the AAV-specific cytotoxic T lymphocytes activation with transaminitis and loss of transgene expression”
From Pre-existing humoral immunity and complement pathway contribute to immunogenicity of adeno-associated virus (AAV) vector in human blood (2022) · cites this paper as [39]
Studies of AAV immunogenicity focused mainly on adaptive immune responses against AAV-transduced hepatocytes.
“therefore studies of AAV immunogenicity focused mainly on the adaptive immune responses against AAV-transduced hepatocytes (38, 39).”
From Pre-existing humoral immunity and complement pathway contribute to immunogenicity of adeno-associated virus (AAV) vector in human blood (2022) · cites this paper as [39]
Vectors rich in CpG motifs result in failure to achieve sustained expression, owing to activation of capsid specific CD8+ T cells.
“Moreover, a recent meta-analysis of clinical trials using hepatic AAV gene transfer concluded that vectors rich in CpG motifs results in failure to achieve sustained expression, owing to activation of capsid specific CD8+ T cells (19–22).”
From Effect of CpG Depletion of Vector Genome on CD8+ T Cell Responses in AAV Gene Therapy (2021) · cites this paper as [19]
Antibody formation against capsid was also not impacted by CpG depletion in clinical trials.
“Antibody formation against capsid was also not impacted by CpG depletion in clinical trials (19, 57).”
From Effect of CpG Depletion of Vector Genome on CD8+ T Cell Responses in AAV Gene Therapy (2021) · cites this paper as [19]
Short-course CCS alone is likely insufficient to inhibit formation of capsid-reactive T cells and rAAV-mediated immune response with systemic high dosages.
“These studies however build evidence that short-course CCS alone is likely to be insufficient to inhibit formation of capsid-reactive T cells (13) and rAAV-mediated immune response with systemic high dosages.”
From Immunomodulation in Administration of RAAV: Preclinical and Clinical Adjuvant Pharmacotherapies (2021) · cites this paper as [13]
In a subsequent study using AAV8, administration of steroids was able to negate this response and maintain therapeutic FIX levels albeit a 50-70% decline from peak levels.
“In the subsequent study using AAV8, administration of steroids was able to negate this response and maintain therapeutic FIX levels albeit a 50-70% decline from peak levels (13).”
From Immunomodulation in Administration of RAAV: Preclinical and Clinical Adjuvant Pharmacotherapies (2021) · cites this paper as [13]
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Self-citation
- Authors
- Nathwani, A. C., Reiss, U. M., Tuddenham, E. G. D., Rosales, C., Chowdary, P., McIntosh, J., Della Peruta, M., Lheriteau, E., Patel, N., Raj, D., Riddell, A., Pie, J., Rangarajan, S., Bevan, D., Recht, M., Shen, Y.-M., Halka, K. G., Basner-Tschakarjan, E., Mingozzi, F., High, K. A., Allay, J., Kay, M. A., Ng, C. Y. C., Zhou, J., Cancio, M., Morton, C. L., Gray, J. T., Srivastava, D., Nienhuis, A. W., & Davidoff, A. M.
- Affiliations
- NHS Blood and Transplant (GB)
- Royal Free London NHS Foundation Trust (GB)
- University College London (GB)
- St Thomas' Hospital (GB)
- Oregon Health & Science University (US)
- The University of Texas Southwestern Medical Center (US)
- Children's Hospital of Philadelphia (US)
- St. Jude Children's Research Hospital (US)
- Stanford Medicine (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2014-11-20
- Volume
- 371
- Issue
- 21
- Pages
- 1994-2004
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC4278802
- OpenAlex
- W1969271703
- Cited by
- 1,273
- References
- 17
- Citations by year
- 2026: 44 · 2025: 64 · 2024: 80 · 2023: 99 · 2022: 118 · 2021: 119 · 2020: 133 · 2019: 125 · 2018: 139 · 2017: 144 · 2016: 108 · 2015: 92 · 2014: 2 · 2013: 4
- FWCI
- 81.02
- 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)
- HAL (submittedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Assisi Foundation of Memphis
- NHS Blood and Transplant
- American Lebanese Syrian Associated Charities
- National Institute for Health and Care Research (RP-PG-0310-1001, NF-SI-0513-10071)
- University College London
- University College London Hospitals NHS Foundation Trust
- Medical Research Council
- National Heart, Lung, and Blood Institute (HL094396, R01HL094396, R01HL073838, R01HL064274)
- National Cancer Institute (P30CA021765)
- Topics
- Health Sciences › Medicine › Hematology › Hemophilia Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- hemophilia B, AAV8 vector, self-complementary AAV, dose-response relationship, long-term safety, late toxicity, alanine aminotransferase elevation, bleeding events
- MeSH terms
- Dependovirus, Adult, Alanine Transaminase, Hemophilia B, Factor IX, Follow-Up Studies, Genetic Vectors, Humans, Infusions, Intravenous, Male, Middle Aged, Genetic Therapy, Gene Expression, Transgenes, Young Adult
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