期刊
MOLECULAR THERAPY
卷 26, 期 1, 页码 304-319出版社
CELL PRESS
DOI: 10.1016/j.ymthe.2017.09.006
关键词
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资金
- National Defense Science and Engineering Graduate Fellowship
- UC Berkeley Graduate Division Fellowship
- NIH [R01 EY022975]
- National Science Foundation Graduate Fellowship
- UC Berkeley Dissertation Fellowship
- NATIONAL EYE INSTITUTE [R01EY022975] Funding Source: NIH RePORTER
Directed evolution continues to expand the capabilities of complex biomolecules for a range of applications, such as adeno-associated virus vectors for gene therapy; however, advances in library design and selection strategies are key to develop variants that overcome barriers to clinical translation. To address this need, we applied structure-guided SCHEMA recombination of the multimeric adeno-associated virus (AAV) capsid to generate a highly diversified chimeric library with minimal structural disruption. A stringent in vivo Cre-dependent selection strategy was implemented to identify variants that transduce adult neural stem cells (NSCs) in the subventricular zone. A novel variant, SCH9, infected 60% of NSCs and mediated 24-fold higher GFP expression and a 12-fold greater transduction volume than AAV9. SCH9 utilizes both galactose and heparan sulfate as cell surface receptors and exhibits increased resistance to neutralizing antibodies. These results establish the SCHEMA library as a valuable tool for directed evolution and SCH9 as an effective gene delivery vector to investigate subventricular NSCs.
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