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

Katja Pekrun, Gustavo De Alencastro, Qing Jun Luo, Jun Liu, Youngjin Kim, Sean Nygaard, Feorillo Galivo, Feijie Zhang, Ren Song, Matthew R. Tiffany, Jianpeng Xu, Matthias Hebrok, Markus Grompe, Mark A. Kay

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere131610
JournalJCI Insight
Volume4
Issue number22
DOIs
StatePublished - Nov 14 2019

ASJC Scopus subject areas

  • Medicine(all)

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    Pekrun, K., De Alencastro, G., Luo, Q. J., Liu, J., Kim, Y., Nygaard, S., Galivo, F., Zhang, F., Song, R., Tiffany, M. R., Xu, J., Hebrok, M., Grompe, M., & Kay, M. A. (2019). Using a barcoded AAV capsid library to select for clinically relevant gene therapy vectors. JCI Insight, 4(22), [e131610]. https://doi.org/10.1172/jci.insight.131610