ArticleMolecular therapy. Methods & clinical development2025
Directed evolution of liver-detargeted AAV vectors for systemic gene delivery to skeletal muscle and heart.
Article in Molecular therapy. Methods & clinical development, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- AAV Vector Toolkit for the Delivery and Expression of the Artificial microRNA in the Murine Heart.Biotech (Basel (Switzerland)) · 2026Article
- Engineering novel AAV capsids by broadly attenuated and subsequent muscle-specific tropism in mice and NHPs.Molecular therapy. Advances · 2026Article
- AAV2 Crosslinks Actin Filaments: Implications for AAV Gene Therapy Vector Design.bioRxiv : the preprint server for biology · 2026Article
- Adeno-Associated Virus Toxicity in Duchenne Muscular Dystrophy: Mechanisms and Clinical Considerations.Genes · 2026Review
- Article
- Bridging science and hope: the evolving story of gene therapy for neuromuscular diseases.Frontiers in cell and developmental biology · 2026Review
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Authors and funding
19 authors.
Funding
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Abstract
Adeno-associated virus (AAV) gene therapies that require systemic administration of high vector doses are associated with hepatotoxicity risk, given the liver tropism of most AAV vectors. We combined screening of natural serotypes, targeted mutagenesis, and directed evolution to identify liver-detargeted muscle-tropic capsids. We found that AAVhu.32 is liver-detargeted compared to AAV9, and AAV5 exhibits high skeletal muscle biodistribution albeit with low transgene expression. Following two rounds of peptide insertion library-based directed evolution of AAV9.AAA (a previously described variant) and AAV5, we identified peptides NVG7 and NVG13, respectively, that confer increased muscle transduction compared to the base capsid with liver-detargeting compared to AAV9 in mouse. In non-human primate (NHP), the liver-detargeted profile of these capsids was confirmed in a pooled capsid study and via comparison to AAV9 NHP literature data. Incorporating AAA.NVG7 into AAVhu.32 led to further improved transduction in mouse heart and brain. The structure and phenotype of the loop insertion in AAV9.AAA.NVG7 is dependent on the sequence of an adjacent loop in a case of sign epistasis between the two sites. These capsids may provide an improved safety profile and increased activity in muscle compared to current AAV capsids.
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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.