Cross-species evolution of a highly potent AAV variant for therapeutic gene transfer and genome editing.

TitleCross-species evolution of a highly potent AAV variant for therapeutic gene transfer and genome editing.
Publication TypeJournal Article
Year of Publication2022
AuthorsTJ Gonzalez, KE Simon, LO Blondel, MM Fanous, AL Roger, MS Maysonet, GW Devlin, TJ Smith, DK Oh, LP Havlik, RM Castellano Rivera, JA Piedrahita, MK ElMallah, CA Gersbach, and A Asokan
JournalNature Communications
Volume13
Start Page5947
Issue1
Date Published10/2022
Abstract

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 strong rationale for potential clinical translation into human gene therapies. We envision that ccAAV vectors may not only improve predictive modeling in preclinical studies, but also clinical translatability by broadening the therapeutic window of AAV based gene therapies.

DOI10.1038/s41467-022-33745-4
Short TitleNature Communications