Adeno‐associated virus (AAV) vectors in gene therapy: immune challenges and strategies to circumvent them
Abstract
SUMMARY: AAV‐based gene transfer protocols have shown remarkable success when directed to immune‐privileged sites such as for retinal disorders like Lebers congenital amaurosis. In contrast, AAV‐mediated gene transfer into liver or muscle tissue for diseases such as hemophilia B, α1 anti‐trypsin deficiency and muscular dystrophy has demonstrated a decline in gene transfer efficacy over time. It is now known that in humans, AAV triggers specific pathways that recruit immune sensors. These factors initiate an immediate reaction against either the viral capsid or the vector encoded protein as part of innate immune response or to produce a more specific adaptive response that generates immunological memory. The vector‐transduced cells are then rapidly destroyed due to this immune activation. However, unlike other viral vectors, AAV is not immunogenic in murine models. Its immunogenicity becomes apparent only in large animal models and human subjects. Moreover, humans are natural hosts to AAV and exhibit a high seroprevalence against AAV vectors. This limits the widespread application of AAV vectors into patients with pre‐existing neutralising antibodies or memory T cells. To address these issues, various strategies are being tested. Alternate serotype vectors (AAV1‐10), efficient expression cassettes, specific tissue targeting, immune‐suppression and engineered capsid variants are some approaches proposed to minimise this immune stimulation. In this review, we have summarised the nature of the immune response documented against AAV in various pre‐clinical and clinical settings and have further discussed the strategies to evade them. Copyright © 2013 John Wiley & Sons, Ltd.
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Applying a different AAV serotype for each readministration typically alleviates the immune reaction.
“Applying a different AAV serotype for each readministration typically alleviates this reaction.”
From Viral Vector Systems for Gene Therapy: A Comprehensive Literature Review of Progress and Biosafety Challenges (2020) · cites this paper as [60]
Several gene clinical trials have revealed that AAV vectors do not stimulate a heightened immune response.
“Moreover, several gene clinical trials have revealed that AAV vectors do not stimulate a heightened immune response.”
From Viral Vector Systems for Gene Therapy: A Comprehensive Literature Review of Progress and Biosafety Challenges (2020) · cites this paper as [60]
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Self-citation
- Authors
- Hareendran, S., Balakrishnan, B., Sen, D., Kumar, S., Srivastava, A., & Jayandharan, G. R.
- Affiliations
- Christian Medical College, Vellore (IN)
- Corresponding author
- Jayandharan, Giridhara R.
- ORCID
- Venue
- Reviews in Medical Virology
- Publisher
- Wiley
- Published
- 2013-09-10
- Volume
- 23
- Issue
- 6
- Pages
- 399-413
- ISSN
- 1052-9276 (ISSN-L)
- 1099-1654
- OpenAlex
- W1822742328
- Cited by
- 113
- References
- 98
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 13 · 2023: 11 · 2022: 4 · 2021: 8 · 2020: 10 · 2019: 6 · 2018: 7 · 2017: 11 · 2016: 7 · 2015: 11 · 2014: 10 · 2013: 2
- FWCI
- 1.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Reviews in Medical Virology (publishedVersion)
- PubMed (publishedVersion)
- 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
- adeno-associated virus vectors, AAV gene therapy, innate immune response, adaptive immune response, immunological memory, AAV serotypes, neutralizing antibodies, AAV capsid engineering, tissue-specific gene targeting, immunosuppression, Leber congenital amaurosis, hemophilia B, alpha-1 antitrypsin deficiency, muscular dystrophy
- MeSH terms
- Dependovirus, Adenoviridae Infections, Animals, Antibodies, Viral, Drug Carriers, Genetic Vectors, Humans, Immunity, Innate, Genetic Therapy, Seroepidemiologic Studies, Adaptive Immunity
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