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Adenovirus-Associated Virus Vector–Mediated Gene Transfer in Hemophilia B
Open accessAbstract
BACKGROUND: Hemophilia B, an X-linked disorder, is ideally suited for gene therapy. We investigated the use of a new gene therapy in patients with the disorder. METHODS: We infused a single dose of a serotype-8-pseudotyped, self-complementary adenovirus-associated virus (AAV) vector expressing a codon-optimized human factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco) in a peripheral vein in six patients with severe hemophilia B (FIX activity, <1% of normal values). Study participants were enrolled sequentially in one of three cohorts (given a high, intermediate, or low dose of vector), with two participants in each group. Vector was administered without immunosuppressive therapy, and participants were followed for 6 to 16 months. RESULTS: AAV-mediated expression of FIX at 2 to 11% of normal levels was observed in all participants. Four of the six discontinued FIX prophylaxis and remained free of spontaneous hemorrhage; in the other two, the interval between prophylactic injections was increased. Of the two participants who received the high dose of vector, one had a transient, asymptomatic elevation of serum aminotransferase levels, which was associated with the detection of AAV8-capsid-specific T cells in the peripheral blood; the other had a slight increase in liver-enzyme levels, the cause of which was less clear. Each of these two participants received a short course of glucocorticoid therapy, which rapidly normalized aminotransferase levels and maintained FIX levels in the range of 3 to 11% of normal values. CONCLUSIONS: Peripheral-vein infusion of scAAV2/8-LP1-hFIXco resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype, with few side effects. Although immune-mediated clearance of AAV-transduced hepatocytes remains a concern, this process may be controlled with a short course of glucocorticoids without loss of transgene expression. (Funded by the Medical Research Council and others; ClinicalTrials.gov number, NCT00979238.).
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“the presence of pre-existing antibodies has been correlated with decreased efficacy of gene therapy in clinical trials where the route of administration exposes vector to serum.26,30,31”
From Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates (2015) · cites this paper as [30]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“NABs are often the most commonly invoked exclusion criterion for patent enrollment.30”
From Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates (2015) · cites this paper as [30]
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“liver-directed therapies resulting in liver transaminase elevation, which coincides with decreased factor IX (FIX) transgene expression, likely due to AAV capsid-specific cytotoxic T cells destroying transduced hepatocytes (12, 13).”
From Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses (2021) · cites this paper as [13]
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“As a result, AAV clinical successes to date have involved delivery either to immune privileged regions or to subjects lacking apparent AAV immunological memory.8–14,30,42”
From Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates (2015) · cites this paper as [30]
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“Finally, certain host responses have only been observed with very high doses of intravenous AAV, suggesting a threshold effect for these host reactions [19–21].”
From Immunogenicity of Recombinant Adeno-Associated Virus (AAV) Vectors for Gene Transfer (2023) · cites this paper as [21]
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“Moreover, administration of intermediate doses of AAV resulted in detectable circulating capsid-specific T cells but transaminase elevation and loss of transgene expression were not observed [21].”
From Immunogenicity of Recombinant Adeno-Associated Virus (AAV) Vectors for Gene Transfer (2023) · cites this paper as [21]
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“In summary, the transgene immune response is mostly observed in patients with no residual protein expression; therefore, clinical studies preferably choose subjects with missense mutation or subjects with no response in protein replacement therapy [21, 24].”
From Immunogenicity of Recombinant Adeno-Associated Virus (AAV) Vectors for Gene Transfer (2023) · cites this paper as [21]
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“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 [57]
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“This led to the requirement for immunosuppression to maintain transgene expression in patients treated with AAVs, further complicating the therapeutic impact.”
From Modulating immune responses to AAV by expanded polyclonal T-regs and capsid specific chimeric antigen receptor T-regulatory cells (2021) · cites this paper as [6]
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“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 [65]
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“Several strategies have been employed to overcome the immune response, including liver targeting to induce immune tolerance [17,18] and the use of steroids to inhibit T cell responses against the capsid to provide durable transgene expression [18,19] being the most well-known methods in clinical and preclinical models…”
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Metadata
- Authors
- Nathwani, A. C., Tuddenham, E. G. D., Rangarajan, S., Rosales, C., McIntosh, J., Linch, D. C., Chowdary, P., Riddell, A., Pie, A. J., Harrington, C., O'Beirne, J., Smith, K., Pasi, J., Glader, B., Rustagi, P., Ng, C. Y. C., Kay, M. A., Zhou, J., Spence, Y., Morton, C. L., Allay, J., Coleman, J., Sleep, S., Cunningham, J. M., Srivastava, D., Basner-Tschakarjan, E., Mingozzi, F., High, K. A., Gray, J. T., Reiss, U. M., Nienhuis, A. W., & Davidoff, A. M.
- Affiliations
- NHS Blood and Transplant (GB)
- Basingstoke and North Hampshire Hospital (GB)
- University College London (GB)
- Queen Mary University of London (GB)
- Stanford Medicine (US)
- St. Jude Children's Research Hospital (US)
- University of Chicago (US)
- Children's Hospital of Philadelphia (US)
- ORCID
- Nathwani, Amit C.
- Tuddenham, Edward G.D.
- Rangarajan, Savita
- Rosales, Cecilia
- McIntosh, Jenny
- Linch, David C.
- Chowdary, Pratima
- Riddell, Anne
- Pasi, John
- Glader, Bertil
- Ng, Catherine Y.C.
- Kay, Mark A.
- Morton, Christopher L.
- Cunningham, John M.
- Mingozzi, Federico
- High, Katherine A.
- Gray, John T.
- Reiss, Ulrike M.
- Davidoff, Andrew M.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2011-12-22
- Volume
- 365
- Issue
- 25
- Pages
- 2357-2365
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC3265081
- OpenAlex
- W2122304523
- Cited by
- 1,864
- References
- 27
- Citations by year
- 2026: 69 · 2025: 84 · 2024: 99 · 2023: 99 · 2022: 119 · 2021: 103 · 2020: 128 · 2019: 116 · 2018: 123 · 2017: 132 · 2016: 128 · 2015: 164 · 2014: 184 · 2013: 185 · 2012: 122
- FWCI
- 108.53
- 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)
- ePrints Soton (University of Southampton) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Assisi Foundation of Memphis
- St. Jude Children's Research Hospital
- NHS Blood and Transplant
- American Lebanese Syrian Associated Charities
- National Institute for Health and Care Research (NF-SI-0507-10370, RP-PG-0310-1001)
- University College London
- Medical Research Council
- National Heart, Lung, and Blood Institute (HL094396, R01HL094396, R01HL073838, R01HL064274)
- 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, gene therapy, AAV8, factor IX, glucocorticoid therapy, aminotransferase elevation, bleeding phenotype, hepatocytes
- MeSH terms
- Dependovirus, Adult, Hemophilia B, Factor IX, Genetic Vectors, Humans, Infusions, Intravenous, Middle Aged, Genetic Therapy, Transgenes
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