biostudies-literatureGonzalez TJNICHD NIH HHSNIAMS NIH HHSU.S. Department of Health & Human Services | National Institutes of Health5947https://www.ebi.ac.uk/biostudies/studies/S-EPMC9548504biostudies-literatureUnknown13(1)Recombinant adeno-associated viral (AAV) vectors are a promising gene delivery platform, but ongoing clinical trials continue to highlight a relatively narrow therapeutic window. Effective clinical translation is confounded, at least in part, by differences in AAV biology across animal species. Here, we tackle this challenge by sequentially evolving AAV capsid libraries in mice, pigs and macaques. We discover a highly potent, cross-species compatible variant (AAV.cc47) that shows improved attributes benchmarked against AAV serotype 9 as evidenced by robust reporter and therapeutic gene expression, Cre recombination and CRISPR genome editing in normal and diseased mouse models. Enhanced transduction efficiency of AAV.cc47 vectors is further corroborated in macaques and pigs, providing a strNature communicationsCross-species evolution of a highly potent AAV variant for therapeutic gene transfer and genome editing.PMC9548504UH3AR075336UH3 AR075336R01 HD099486Maysonet MSBlondel LOFanous MMCastellanos Rivera RMElMallah MKOh DKHavlik LPGersbach CAAsokan AGonzalez TJPiedrahita JARoger ALSimon KESmith TJDevlin GWfalseCross-species evolution of a highly potent AAV variant for therapeutic gene transfer and genome editing.Recombinant adeno-associated viral (AAV) vectors are a promising gene delivery platform, but ongoing clinical trials continue to highlight a relatively narrow therapeutic window. Effective clinical translation is confounded, at least in part, by differences in AAV biology across animal species. Here, we tackle this challenge by sequentially evolving AAV capsid libraries in mice, pigs and macaques. We discover a highly potent, cross-species compatible variant (AAV.cc47) that shows improved attributes benchmarked against AAV serotype 9 as evidenced by robust reporter and therapeutic gene expression, Cre recombination and CRISPR genome editing in normal and diseased mouse models. Enhanced transduction efficiency of AAV.cc47 vectors is further corroborated in macaques and pigs, providing a str2022-01-01T00:00:00Z2022 Oct2025-04-04T22:36:02.796Z2024-12-04T12:08:15.342ZS-EPMC95485043621036410.1038/s41467-022-33745-4