The DOI matches its Crossref record; 27 of the 27 references it cites were found in a registry or an index.
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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In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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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Self-citationDystrophin Immunity in Duchenne's Muscular Dystrophy
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Self-citationDarby, S. C., Kan, S. W., Spooner, R. J. D., Giangrande, P. L. F., Hill, F. G. H., Hay, C. R. M., Lee, C. A., Ludlam, C. A., & Williams, M. (2007) · Blood · doi:10.1182/blood-2006-10-050435 · Cited by 511
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Self-citationSnyder, R. O., Miao, C., Meuse, L., Tubb, J., Donahue, B. A., Lin, H.-F., Stafford, D. W., Patel, S., Thompson, A. R., Nichols, T., et al. (1999) · Nature Medicine · doi:10.1038/4751 · Cited by 409
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Adeno-associated virus vector as a platform for gene therapy delivery
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Long-Term Safety and Efficacy of Factor IX Gene Therapy in Hemophilia B
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., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1407309 · Cited by 1,273
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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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