Oversized AAV Transductifon Is Mediated via a DNA-PKcs-independent, Rad51C-dependent Repair Pathway
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A drawback of gene therapy using adeno-associated virus (AAV) is the DNA packaging restriction of the viral capsid (<4.7 kb). Recent observations demonstrate oversized AAV genome transduction through an unknown mechanism. Herein, AAV production using an oversized reporter (6.2 kb) resulted in chloroform and DNase-resistant particles harboring distinct "fragment" AAV (fAAV) genomes (5.0, 2.4, and 1.6 kb). Fractionation experiments determined that only the larger "fragments" mediated transduction in vitro, and relatively efficient transduction was also demonstrated in the muscle, the eye, and the liver. In contrast with concatemerization-dependent large-gene delivery by split AAV, fAAV transduction is independent of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) in vitro and in vivo while disproportionately reliant on the DNA strand-annealing protein Rad51C. Importantly, fAAV's unique dependence on DNA repair proteins, compared with intact AAV, strongly suggests that the majority of oversized AAV transduction is mediated by fragmented genomes. Although fAAV transduction is less efficient than intact AAV, it is enhanced fourfold in muscle and sevenfold in the retina compared with split AAV transduction. Furthermore, fAAV carrying codon-optimized therapeutic dysferlin cDNA in a 7.5 kb expression cassette restored dysferlin levels in a dystrophic model. Collectively, oversized AAV genome transduction requires unique DNA repair pathways and offers an alternative, more efficient strategy for large-gene therapy.
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Transduction by oversized vectors depends on the activity of the strand-annealing protein Rad51C but is independent of the catalytic subunit of DNA-dependent protein kinase.
“Samulski and colleagues reported that transduction by oversized vectors depends on the activity of the strand-annealing protein Rad51C but is independent of the catalytic subunit of DNA-dependent protein kinase. 34”
From Expressing Transgenes That Exceed the Packaging Capacity of Adeno-Associated Virus Capsids (2016) · cites this paper as [34]
Trans-splicing vector-pair systems do not always outperform single oversized vectors; Hirsch et al. reported higher expression both in vitro and in vivo with a single oversized genome vector compared with a trans-splicing system.
“similar to dual overlapping vectors, trans-splicing vector-pair systems do not always outperform single oversized vectors. For instance, Hirsch et al. 34 reported higher expression both in vitro (C2C12 myoblasts and myotubules) and in vivo with a single oversized genome vector when compared with a transsplicing system. 34”
From Expressing Transgenes That Exceed the Packaging Capacity of Adeno-Associated Virus Capsids (2016) · cites this paper as [34]
Circularization is an intramolecular event and is probably more efficient than intermolecular concatemerization.
“Because such a circularization is an intramolecular event, it is probably more efficient than intermolecular concatemerization. 34,49,58”
From Expressing Transgenes That Exceed the Packaging Capacity of Adeno-Associated Virus Capsids (2016) · cites this paper as [34]
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- Authors
- Hirsch, M. L., Li, C., Bellon, I., Yin, C., Chavala, S., Pryadkina, M., Richard, I., & Samulski, R. J.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Hirsch, Matthew L
- Samulski, Richard Jude
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2013-12
- Volume
- 21
- Issue
- 12
- Pages
- 2205-2216
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC3863795
- OpenAlex
- W2125901877
- Cited by
- 62
- References
- 46
- Citations by year
- 2025: 5 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 4 · 2020: 3 · 2019: 5 · 2018: 4 · 2017: 12 · 2016: 5 · 2015: 8 · 2014: 7 · 2013: 1
- FWCI
- 4.64
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- HAL (submittedVersion)
- UNC Libraries
- Funders
- Jain Foundation
- National Institutes of Health (5u54ar056953-05)
- National Eye Institute (K08EY021171)
- National Cancer Institute (P30CA016086)
- National Institute of Allergy and Infectious Diseases (R01AI072176, R01AI080726, AI072176)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK084033, DK084033)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54-AR056953)
- 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, DNA-PKcs, RAD51C, DNA repair pathways, gene therapy vectors, dysferlin, Duchenne muscular dystrophy, in vivo transduction
- MeSH terms
- Dependovirus, Animals, Capsid, Cricetulus, Disease Models, Animal, DNA-Binding Proteins, DNA, Viral, Eye, Genetic Vectors, HeLa Cells, Humans, Liver, Muscle Proteins, Muscles, Nucleic Acid Conformation, Transduction, Genetic, Genetic Therapy, CHO Cells, Genome, Viral, Genes, Reporter, Muscle, Skeletal, DNA Packaging, Rad51 Recombinase, Mice, HEK293 Cells
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