ArticleThe Journal of clinical investigation2015
Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy.
Article in The Journal of clinical investigation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 242 papers, 2 of them syntheses that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
242 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Changing trends in the development of AAV-based gene therapies: a meta-analysis of past and present therapies.Gene therapy · 2023Pooled it
- rAAV immunogenicity, toxicity, and durability in 255 clinical trials: A meta-analysis.Frontiers in immunology · 2022Pooled it
- In vivo topical gene therapy for recessive dystrophic epidermolysis bullosa: a phase 1 and 2 trial.Nature medicine · 2022Trial
- Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A.The New England journal of medicine · 2021Trial
- Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant.The New England journal of medicine · 2017Trial
- Defining the safety and efficacy of liver-directed AAV gene therapy using a human liver tissue-equivalent platform.Molecular therapy. Advances · 2026Article
- Long-read target enrichment sequencing for rAAV integration site analysis in engineered clones with targeted viral insertion.Molecular therapy. Nucleic acids · 2026Article
- Advances in gene transfer technologies: comparing viral and non-viral vectors for therapeutic applications.3 Biotech · 2026Review
- Recent advances in treating age-related macular degeneration and diabetic retinopathy: Current therapies and emerging novel approaches.GeroScience · 2026Review
- AAV Vectors in Regenerative Medicine and Cellular Reprogramming: Potential, Pitfalls, and Specificity Constraints.International journal of molecular sciences · 2026Review
- Structural basis of liver de-targeting and neuronal tropism of CNS-targeted AAV capsids.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- Optimized AAV vector enables potent therapeutic rescue of inherited glycosylphosphatidylinositol deficiency in mice.Molecular therapy. Advances · 2026Article
- Systemic delivery of AAV-GFM1 corrects COXPD1 molecular alterations in Gfm1EMBO molecular medicine · 2026Article
- Long-term comparative analysis of AAV9-mediated gene replacement therapies for spinal muscular atrophy in mice.Nature communications · 2026Article
- Optimized lentivirus-derived virus-like particles for efficient delivery of Cas9-based genome editors.Nucleic acids research · 2026Article
- STARR-CRAAVT: A platform to identify cell type-specific regulatory elements for next-generation gene therapy.iScience · 2026Article
- Transforming Hemophilia Management: Lessons from Gene Therapy Clinical Trials.Molecular biotechnology · 2026Review
- RAAVioli: A comprehensive approach to characterizing AAV vector integrations and rearrangements.Molecular therapy. Advances · 2026Article
- Comparison of AAV9-driven motor neuron transduction following different CNS-directed delivery methods in mice.Scientific reports · 2026Article
- Gene, genetics and genetic medicines in gastroenterology: Current status and its future.World journal of gastroenterology · 2026Review
182 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors.
Funding
Abstract
The use of adeno-associated virus (AAV) as a gene therapy vector has been approved recently for clinical use and has demonstrated efficacy in a growing number of clinical trials. However, the safety of AAV as a vector has been challenged by a single study that documented hepatocellular carcinoma (HCC) after AAV gene delivery in mice. Most studies have not noted genotoxicity following AAV-mediated gene delivery; therefore, the possibility that there is an association between AAV and HCC is controversial. Here, we performed a comprehensive study of HCC in a large number of mice following therapeutic AAV gene delivery. Using a sensitive high-throughput integration site-capture technique and global expressional analysis, we found that AAV integration into the RNA imprinted and accumulated in nucleus (Rian) locus, and the resulting overexpression of proximal microRNAs and retrotransposon-like 1 (Rtl1) were associated with HCC. In addition, we demonstrated that the AAV vector dose, enhancer/promoter selection, and the timing of gene delivery are all critical factors for determining HCC incidence after AAV gene delivery. Together, our results define aspects of AAV-mediated gene therapy that influence genotoxicity and suggest that these features should be considered for design of both safer AAV vectors and gene therapy studies.
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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.