ArticleMolecular therapy : the journal of the American Society of Gene Therapy2013
Oversized AAV transductifon is mediated via a DNA-PKcs-independent, Rad51C-dependent repair pathway.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 62 citations in OpenAlex.
- Evaluation of the loading capacity and patterns of packaged DNA in AAV genomes of different sizes using long-read sequencing.Molecular therapy. Methods & clinical development · 2025Article
- Gene therapy for age-related macular degeneration: a promising frontier in vision preservation.Cell communication and signaling : CCS · 2025Review
- Use of an oversized AAV8 vector for CPS1 deficiency results in long-term survival and ammonia control.Molecular therapy. Nucleic acids · 2025Article
- Double-strand break repair pathways differentially affect processing and transduction by dual AAV vectors.Nature communications · 2025Article
- Cryo-EM structures of the membrane repair protein dysferlin.Nature communications · 2024Article
- Engineering of the AAV-Compatible Hair Cell-Specific Small-Size Myo15 Promoter for Gene Therapy in the Inner Ear.Research (Washington, D.C.) · 2024Article
- Inhibition of DNA-dependent protein kinase catalytic subunit boosts rAAV transduction of polarized human airway epithelium.Molecular therapy. Methods & clinical development · 2023Article
- Chemical Epigenetic Regulation of Adeno-Associated Virus Delivered Transgenes.Human gene therapy · 2023Article
- AAV vectors: The Rubik's cube of human gene therapy.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Review
- Interindividual variability in transgene mRNA and protein production following adeno-associated virus gene therapy for hemophilia A.Nature medicine · 2022Article
- Molecular analysis of AAV5-hFVIII-SQ vector-genome-processing kinetics in transduced mouse and nonhuman primate livers.Molecular therapy. Methods & clinical development · 2022Article
- Redefining the architecture of ferlin proteins: Insights into multi-domain protein structure and function.PloS one · 2022Article
- Advances in designing Adeno-associated viral vectors for development of anti-HBV gene therapeutics.Virology journal · 2021Review
- Engineering adeno-associated virus vectors for gene therapy.Nature reviews. Genetics · 2020Review
- Overloaded Adeno-Associated Virus as a Novel Gene Therapeutic Tool for Otoferlin-Related Deafness.Frontiers in molecular neuroscience · 2020Article
- DualHuman gene therapy · 2019Article
- Suppression of Choroidal Neovascularization by AAV-Based Dual-Acting Antiangiogenic Gene Therapy.Molecular therapy. Nucleic acids · 2019Article
- Article
- Emerging Issues in AAV-MediatedMolecular therapy. Methods & clinical development · 2018Review
- Inhibition of antigen presentation during AAV gene therapy using virus peptides.Human molecular genetics · 2018Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.