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JCI Insight. 2019 Nov 14;4(22). pii: 131610. doi: 10.1172/jci.insight.131610.

Using a barcoded AAV capsid library to select for clinically relevant gene therapy vectors.

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Departments of Pediatrics and Genetics, Stanford University, Stanford, California, USA.
UCSF Diabetes Center, UCSF, San Francisco, California, USA.
Oregon Stem Cell Center, Oregon Health & Science University (OHSU), Portland, Oregon, USA.


While gene transfer using recombinant adeno-associated viral (rAAV) vectors has shown success in some clinical trials, there remain many tissues that are not well transduced. Because of the recent success in reprogramming islet-derived cells into functional β cells in animal models, we constructed 2 highly complex barcoded replication competent capsid shuffled libraries and selected for high-transducing variants on primary human islets. We describe the generation of a chimeric AAV capsid (AAV-KP1) that facilitates transduction of primary human islet cells and human embryonic stem cell-derived β cells with up to 10-fold higher efficiency compared with previously studied best-in-class AAV vectors. Remarkably, this chimeric capsid also enabled transduction of both mouse and human hepatocytes at very high levels in a humanized chimeric mouse model, thus providing a versatile vector that has the potential to be used in both preclinical testing and human clinical trials for liver-based diseases and diabetes.


Diabetes; Embryonic stem cells; Gene therapy; Therapeutics

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