Can Adeno-Associated Viral Vectors Deliver Effectively Large Genes?
Abstract
Gene therapy with adeno-associated viral (AAV) vectors has reached the clinical stage for many inherited and acquired diseases. However, due to a cargo capacity limited to <5 kb, AAV-mediated treatment of diseases that require transfer of larger genes still appears elusive. This is a major drawback of a platform that has otherwise been repeatedly found to be safe and effective. Thus, great efforts have been directed toward the identification of strategies to overcome this limitation. Among the most studied approaches is the use of dual vectors, in which a transgene is split across two separate AAV vectors. Mechanisms acting at either the DNA, pre-mRNA, or protein levels have been explored to restore full-length transgene expression in infected cells. Here, we will review them as well as additional strategies developed to deliver large genes with AAV. We discuss the pros and cons of these strategies and the aspects that still need to be addressed.
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Dual/triple AAV vectors can produce aberrant protein products from erroneous reassembly and/or untoward expression of individual split transgenes.
“For instance, a general issue of dual/triple AAV vectors is the potential production of aberrant protein products from (i) erroneous reassembly and/or from (ii) the untoward expression of individual split transgenes.”
From Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders (2022) · cites this paper as [31]
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- Authors
- Tornabene, P., & Trapani, I.
- Affiliations
- Telethon Institute Of Genetics And Medicine (IT)
- Corresponding author
- Trapani, Ivana
- Venue
- Human Gene Therapy
- Publisher
- SAGE Publications
- Published
- 2020-01-01
- Volume
- 31
- Issue
- 1-2
- Pages
- 47-56
- ISSN
- 1043-0342 (ISSN-L)
- 1557-7422
- OpenAlex
- W2999790225
- Cited by
- 76
- References
- 17
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 8 · 2023: 17 · 2022: 14 · 2021: 12 · 2020: 5
- FWCI
- 1.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Gene Therapy (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
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Keywords
- adeno-associated virus vectors, gene therapy, pre-mRNA splicing
- MeSH terms
- Dependovirus, Animals, Genetic Engineering, Genetic Vectors, Humans, RNA, Messenger, Genetic Therapy, Gene Expression, Gene Transfer Techniques, Transgenes, Trans-Splicing, Genome Size
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