Characterization of Genome Integrity for Oversized Recombinant AAV Vector
Open accessAbstract
Application of recombinant adeno-associated virus (rAAV) in gene therapy has been limited by its packaging capacity. Recent studies suggested that rAAV could achieve persistent transgene expression beyond 4.7-kb packaging limit. To clarify the mechanism leading to transgene expression from oversized rAAV vector, we constructed a series of rAAV vectors with genomes ranging from 2.9 to 7.2 kb. A plasmid replication origin and an ampicillin-resistant marker were included in the vector to facilitate the recovery of circularized, post-transduction AAV genome. Southern dot-blot analysis and silver staining confirmed that rAAVs could be produced at varying vector size. However, the vector yields decreased approximately tenfold for oversized vectors as compared to regular ones. Alkaline Southern blot hybridization suggested that the packaged genomes for oversized vectors were truncated. In the cells transduced by the above vectors, circularized rAAV monomers could be rescued at 24 hours after infection. Few recovered AAV genomes were >5 kb regardless of the initial vector size. In mice receiving the above vectors, larger circularized rAAV genomes could be recovered for oversized vectors at day 21 after vector administration. Our studies suggested that the partially packaged rAAV sequences may complement each other to restore full expression cassette.
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AAV has a strict size cutoff of 5.2 kb.
“other studies [6-8] indicated that intact genomes were not, in fact, packaged in that case [3], and further suggested a strict size cutoff of 5.2 kb.”
From Optimization of AAV expression cassettes to improve packaging capacity and transgene expression in neurons (2014) · cites this paper as [6]
The Discussion supports a physical limit on AAV genome packaging, but gives the limit as less than 5 kb and concludes that a capsid cannot accommodate more than 5,000 nucleotides. It does not support the claimed strict cutoff of 5.2 kb. (LLM, conf=0.88)
Experimental — accuracy not yet measuredrAAV genome-packaging capacity is approximately 5 kb.
“One limitation of rAAVs is that their genome-packaging capacity is only * 5kb.”
From Expressing Transgenes That Exceed the Packaging Capacity of Adeno-Associated Virus Capsids (2016) · cites this paper as [31]
The finding that AAV5 capsids could package intact genomes of up to 8.9 kb in length was not supported by further studies; such genomes were truncated and the packaging capacity of AAV was still limited to genomes substantially smaller than 8.9 kb.
“However, the finding that AAV5 capsids could package intact genomes of up to 8.9 kb in length was not supported by further studies, which found that such genomes were truncated and that the packaging capacity of AAV was still limited to genomes substantially smaller than 8.9 kb. 30-32”
From Expressing Transgenes That Exceed the Packaging Capacity of Adeno-Associated Virus Capsids (2016) · cites this paper as [31]
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- Authors
- Dong, B., Nakai, H., & Xiao, W.
- Affiliations
- Temple University (US)
- University of Pittsburgh (US)
- Corresponding author
- Xiao, Weidong
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2010-01
- Volume
- 18
- Issue
- 1
- Pages
- 87-92
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC2803017
- OpenAlex
- W2049442129
- Cited by
- 230
- References
- 38
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 14 · 2023: 11 · 2022: 16 · 2021: 15 · 2020: 18 · 2019: 17 · 2018: 8 · 2017: 15 · 2016: 13 · 2015: 16 · 2014: 20 · 2013: 9 · 2012: 15
- FWCI
- 7.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL084381, HL080789, HL084381, R01HL080789)
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Viral Infectious Diseases and Gene Expression in Insects
- Keywords
- recombinant adeno-associated virus, genome stability, transgene expression, gene therapy vectors
- MeSH terms
- Dependovirus, Animals, Cell Line, Genetic Vectors, HeLa Cells, Humans, Mice, Inbred C57BL, Genome, Viral, Mice
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