ArticleMolecular therapy : the journal of the American Society of Gene Therapy2024
Development of CNS tropic AAV1-like variants with reduced liver-targeting following systemic administration in mice.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 15 citations in OpenAlex.
- Deep-sequencing-guided library screening and profiling of AAV capsids in the primate retina.Molecular therapy. Advances · 2026Article
- DNA and RNA editing for the therapy of human diseases: current status, challenges, and future prospects.Molecular biomedicine · 2026Review
- Immunogenicity of Gene and Cell Therapies.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2026Review
- Genetic Tools in Rodents to Study Cannabinoid Functions.Current topics in behavioral neurosciences · 2026Review
- Article
- Directed evolution of novel AAV variants using the MCMS library for enhanced CNS tropism and reduced liver targeting in mice.Molecular therapy. Methods & clinical development · 2025Article
- Revolution of AAV in Drug Discovery: From Delivery System to Clinical Application.Journal of medical virology · 2025Review
- The regulation of reporter transgene expression for diverse biological imaging applications.Npj imaging · 2025Review
- AAVolve: Concatenated long-read deep sequencing enables whole capsid tracking during shuffled AAV library selection.Molecular therapy. Methods & clinical development · 2024Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Directed evolution of natural AAV9 using peptide display libraries have been widely used in the search for an optimal recombinant AAV (rAAV) for transgene delivery across the blood-brain barrier (BBB) to the CNS following intravenous ( IV) injection. In this study, we used a different approach by creating a shuffled rAAV capsid library based on parental AAV serotypes 1 through 12. Following selection in mice, 3 novel variants closely related to AAV1, AAV-BBB6, AAV-BBB28, and AAV-BBB31, emerged as top candidates. In direct comparisons with AAV9, our novel variants demonstrated an over 270-fold improvement in CNS transduction and exhibited a clear bias toward neuronal cells. Intriguingly, our AAV-BBB variants relied on the LY6A cellular receptor for CNS entry, similar to AAV9 peptide variants AAV-PHP.eB and AAV.CAP-B10, despite the different bioengineering methods used and parental backgrounds. The variants also showed reduced transduction of both mouse liver and human primary hepatocytes in vivo. To increase clinical translatability, we enhanced the immune escape properties of our new variants by introducing additional modifications based on rational design. Overall, our study highlights the potential of AAV1-like vectors for efficient CNS transduction with reduced liver tropism, offering promising prospects for CNS gene therapies.
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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.