Systemic administration of novel engineered AAV capsids facilitates enhanced transgene expression in the macaque CNS

Background: Adeno-associated virus (AAV) vectors are a promising vehicle for noninvasive gene delivery to the central nervous system via intravenous infusion. However, naturally occurring serotypes have a limited ability to transduce the brain, and translating engineered cap-sids from mice to nonhuman primates has proved challenging.Methods: In this study, we use an mRNA-based directed-evolution strategy in multiple strains of mice as well as a de novo selection in cyn-omolgus macaques to identify families of engineered vectors with increased potency in the brain and decreased tropism for the liver.Findings: We compare the transgene expression capabilities of several engineered vectors and show that while some of our novel macaque -derived variants significantly outperform AAV9 in transducing the ma-caque brain following systemic administration, mouse-derived vari-ants-both those identified in this study and those reported by other groups-universally do not.Conclusions: Together, the results of this work introduce a class of pri-mate-derived engineered AAV capsids with increased therapeutic po-tential and highlight the critical need for using appropriate animal models to both identify and evaluate novel AAVs intended for delivery to the human central nervous system.

Automated summary

In this study, scientists used mRNA-based directed evolution strategy in mice and cynomolgus macaques to identify engineered AAV vectors with increased brain transduction capability and decreased liver tropism. While the macaque-derived variants showed significant improvement in transducing the macaque brain, the mouse-derived variants, both from this study and other groups, were not effective. This study highlights the importance of using appropriate animal models for evaluating novel AAVs intended for CNS delivery.