@article{4c2c291ee1e0437aa098787a22284ba6,
title = "Using a barcoded AAV capsid library to select for clinically relevant gene therapy vectors",
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.",
author = "Katja Pekrun and {De Alencastro}, Gustavo and Luo, {Qing Jun} and Jun Liu and Youngjin Kim and Sean Nygaard and Feorillo Galivo and Feijie Zhang and Ren Song and Tiffany, {Matthew R.} and Jianpeng Xu and Matthias Hebrok and Markus Grompe and Kay, {Mark A.}",
note = "Funding Information: This work was supported by grants from the NIH (U01DK089569 and RO1 AI116698). Human pancreatic islets were provided by the NIDDK-funded Integrated Islet Distribution Program (IIDP) at City of Hope, NIH grant 2UC4DK098085, and the Stanford Islet Research Core. Work in MH{\textquoteright}s laboratory was supported by NIH R01 (DK105831); YK was supported by a Kraft Family Postdoctoral Fellowship. We are deeply indebted to the islet donors and their families for making this study possible. We are grateful to Dirk Grimm and Stephanie Grosse (University of Heidelberg) for supplying this study with the AAV backbone vector and the majority of parental capsid sequences. We thank Javier Alcudia (Stanford Vector Core) for supplying us with several parental capsids and Hiroyuki Nakai (OHSU) for advice on BC library generation. We are indebted to Yan Hang, Heshan Peiris, and Robert Whitener (Stanford University) for help with islet culture, staining, and FACS. We thank Hak Kyun Kim (Stanford University) for help with figure generation, Francesco Puzzo for guidance on statistics, and Paul Valdmanis (University of Washington) for development of the conservation and enrichment analysis. This project was also supported by a NIH Shared Instrumentation Grant (S10-OD010580) from the National Center for Research Resources (NCRR), with significant contribution from Stanford{\textquoteright}s Beckman Center, as well as the Stanford Small Animal Imaging Facility. The authors wish to acknowledge the Stanford Genomics Facility for performing HTS. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the various funding bodies or universities involved. Packaging plasmids of the new capsids described herein must be obtained through an MTA with Stanford University. Publisher Copyright: {\textcopyright} 2019, American Societyfor Clinical Investigation.",
year = "2019",
month = nov,
day = "14",
doi = "10.1172/jci.insight.131610",
language = "English (US)",
volume = "4",
journal = "JCI Insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "22",
}