Using a barcoded AAV capsid library to select for novel clinically relevant gene therapy vectors
| Autor: | Sean Nygaard, Ren Song, Feijie Zhang, Jun Liu, Qing-Jun Luo, Mark A. Kay, Matthias Hebrok, Jianpeng Xu, Markus Grompe, Youngjin Kim, Matthew Tiffany, Katja Pekrun, Gustavo de Alencastro, Feorillo Galivo |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
geography geography.geographical_feature_category viruses Gene transfer Computational biology Biology Vectors in gene therapy Islet Embryonic stem cell 3. Good health law.invention 03 medical and health sciences 0302 clinical medicine Capsid law Recombinant DNA Vector (molecular biology) Reprogramming 030217 neurology & neurosurgery 030304 developmental biology |
| DOI: | 10.1101/683672 |
| Popis: | While gene transfer using recombinant adeno-associated viral (rAAV) vectors have 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 two highly complex barcoded replication competent capsid shuffled libraries and selected for high transducing variants on primary human islets. We describe a chimeric capsid (AAV-KP1) that penetrated and transduced primary human islet cells and human embryonic stem cell derived β-cells with up to 10-fold higher efficiency compared to previously studied best in class AAV vectors. Remarkably, this chimeric capsid was also able to transduce both mouse and human hepatocytes at very high levels in a humanized-chimeric mouse model, thus providing a versatile vector which has the potential to be used in both preclinical testing and human clinical trials for both liver-based diseases and diabetes. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|