AAV-1–mediated gene transfer to skeletal muscle in humans results in dose-dependent activation of capsid-specific T cells
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In a clinical trial for adeno-associated virus serotype 1 (AAV-1)–mediated gene transfer to muscle for lipoprotein lipase (LPL) deficiency, 1 subject from the high-dose cohort experienced a transient increase in the muscle enzyme creatine phosphokinase (CPK) 4 weeks after gene transfer. Simultaneously, after an initial downward trend consistent with expression of LPL, plasma triglyceride levels returned to baseline. We characterized B- and T-cell responses to the vector and the transgene product in the subjects enrolled in this study. IFN-γ enzyme-linked immunosorbent spot (ELISpot) and intracellular cytokine staining assays performed on peripheral blood mononuclear cells (PBMCs) from the subject who experienced the CPK elevation showed the activation of capsid-specific CD4+ and CD8+ T cells. Four of 8 subjects had detectable T-cell responses to capsid with dose-dependent kinetics of appearance. Subjects with detectable T-cell responses to capsid also had higher anti–AAV-1 IgG3 antibody titer. No subject developed B- or T-cell responses to the LPL transgene product. These findings suggest that T-cell responses directed to the AAV-1 capsid are dose-dependent. Whether they also limit the duration of expression of the transgene at higher doses is unclear, and will require additional analyses at later time points.
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In patients receiving intramuscular AAV1 gene therapy with alipogene tiparvovec for lipoprotein lipase deficiency, dose-dependent AAV-specific T cell activation was seen.
“For example, dose-dependent, AAV-specific T cell activation was seen in patients who received intramuscular gene therapy with an AAV1 vector (alipogene tiparvovec, Glybera) for lipoprotein lipase deficiency (Mingozzi et al., 2009; Ferreira et al., 2014).”
From Gene Therapy-Associated Uveitis (GTAU): Understanding and mitigating the adverse immune response in retinal gene therapy (2025) · cites this paper as Mingozzi et al., 2009
The Introduction (p. 1) describes intramuscular AAV-1 gene transfer for lipoprotein lipase deficiency, and the results (p. 3) report capsid-specific T-cell responses in 4 of 8 subjects with dose-dependent timing. Our copy identifies the vector as AAV-1–LPL S447X but does not identify it as alipogene tiparvovec or Glybera, so that part of the attribution is not verified. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe 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 [86]
Other trials have observed T-cell immune responses that did not clear transgene expression, particularly muscle-directed trials.
“In contrast, other trials have observed T-cell immune responses that did not clear transgene expression, particularly muscle-directed trials [86, 90, 91].”
From Immunogenicity of Recombinant Adeno-Associated Virus (AAV) Vectors for Gene Transfer (2023) · cites this paper as [86]
Concurrent clinical trials using i.m. delivery of AAV revealed long-term transgene expression without immune suppression, regardless of significant immune cell infiltration.
“Despite the observation of immune responses after intravenous (i.v.) administration of AAV, concurrent clinical trials using intramuscular (i.m.) delivery of AAV revealed long-term transgene expression without immune suppression, regardless of significant immune cell infiltration.”
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 [9]
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Shirley, J. L., Keeler, G. D., Sherman, A., Zolotukhin, I., Markusic, D. M., Hoffman, B. E., Morel, L. M., Wallet, M. A., Terhorst, C., & Herzog, R. W. (2020) · Molecular Therapy · doi:10.1016/j.ymthe.2019.11.011 · Cited by 79 · see citing works
The Effect of CpG Sequences on Capsid-Specific CD8+ T Cell Responses to AAV Vector Gene Transfer
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Self-citationStrategies to circumvent humoral immunity to adeno-associated viral vectors
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MyD88 Signaling in B Cells Regulates the Production of Th1-dependent Antibodies to AAV
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Humoral immune responses to <scp>AAV</scp> gene therapy in the ocular compartment
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Modulation of CD8+ T cell responses to AAV vectors with IgG-derived MHC class II epitopes
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“For example, dose-dependent, AAV-specific T cell activation was seen in patients who received intramuscular gene therapy with an AAV1 vector (alipogene tiparvovec, Glybera) for lipoprotein lipase deficiency (Mingozzi et al., 2009; Ferreira et al., 2014).”
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Effects of immunosuppression on circulating adeno-associated virus capsid-specific T cells in humans
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- Authors
- Mingozzi, F., Meulenberg, J. J., Hui, D. J., Basner-Tschakarjan, E., Hasbrouck, N. C., Edmonson, S. A., Hutnick, N. A., Betts, M. R., Kastelein, J. J., Stroes, E. S., & High, K. A.
- Affiliations
- Children's Hospital of Philadelphia (US)
- Amsterdam Molecular Therapeutics, Amsterdam, The Netherlands;
- Division of Hematology and Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, PA;
- University of Pennsylvania (US)
- Amsterdam UMC Location University of Amsterdam (NL)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2009-09-03
- Volume
- 114
- Issue
- 10
- Pages
- 2077-2086
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC2744569
- OpenAlex
- W2138117792
- Cited by
- 295
- References
- 42
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 22 · 2023: 17 · 2022: 17 · 2021: 18 · 2020: 11 · 2019: 16 · 2018: 4 · 2017: 8 · 2016: 7 · 2015: 28 · 2014: 19 · 2013: 22 · 2012: 26
- FWCI
- 15.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (T32 HL07439, P01HL078810, T32HL007439, T32HL007150)
- Topics
- 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
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- lipoprotein lipase deficiency, dose-dependent immune response, creatine kinase elevation, CD4+ T cells, CD8+ T cells, vector immunogenicity
- MeSH terms
- Dependovirus, Antibodies, Viral, B-Lymphocytes, Capsid, Creatine Kinase, Dose-Response Relationship, Immunologic, Female, Humans, Immunoglobulin G, Immunoenzyme Techniques, Interferon-gamma, Lipoprotein Lipase, Hyperlipoproteinemia Type I, Lymphocyte Activation, Male, Transduction, Genetic, Triglycerides, Genetic Therapy, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Muscle, Skeletal, Transgenes
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