Development of new adeno-associated virus capsid variants for targeted gene delivery to human cardiomyocytes

Kok, Cindy Y. and Tsurusaki, Shinya and Cabanes-Creus, Marti and Igoor, Sindhu and Rao, Renuka and Skelton, Rhys and Liao, Sophia H.Y. and Ginn, Samantha L. and Knight, Maddison and Scott, Suzanne and Mietzsch, Mario and Fitzsimmons, Rebecca and Miller, Jessica and Mohamed, Tamer M.A. and McKenna, Robert and Chong, James J.H. and Hill, Adam P. and Hudson, James E. and Alexander, Ian E. and Lisowski, Leszek and Kizana, Eddy (2023) Development of new adeno-associated virus capsid variants for targeted gene delivery to human cardiomyocytes. Molecular Therapy - Methods & Clinical Development, 30. pp.459-473. ISSN 23290501

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Recombinant adeno-associated viruses (rAAVs) have emerged as one of the most promising gene therapy vectors that have been successfully used in pre-clinical models of heart disease. However, this has not translated well to humans due to species differences in rAAV transduction efficiency. As a result, the search for human cardiotropic capsids is a major contemporary challenge. We used a capsid-shuffled rAAV library to perform directed evolution in human iPSC-derived cardiomyocytes (hiPSC-CMs). Five candidates emerged, with four presenting high sequence identity to AAV6, while a fifth divergent variant was related to AAV3b. Functional analysis of the variants was performed in vitro using hiPSC-CMs, cardiac organoids, human cardiac slices, non-human primate and porcine cardiac slices, as well as mouse heart and liver in vivo. We showed that cell entry was not the best predictor of transgene expression efficiency. The novel variant rAAV.KK04 was the best-performing vector in human-based screening platforms, exceeding the benchmark rAAV6. None of the novel capsids demonstrate a significant transduction of liver in vivo. The range of experimental models used revealed the value of testing for tropism differences under the conditions of human specificity, bona fide, myocardium and cell type of interest.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 01 May 2024 04:48
Last Modified: 01 May 2024 04:48

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