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

Abstract

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 capsids 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 in a de novo selection in cynomolgus 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 macaque brain following systemic administration, mouse-derived variants—both those identified in this study and those reported by other groups—universally did not.

Conclusions

Together, this work introduces a class of primate-derived engineered AAV capsids with increased therapeutic potential and underscores the critical need for using appropriate animal models to both identify and evaluate novel AAVs intended for delivery to the human central nervous system.

Funding

This work was funded primarily through an anonymous philanthropic gift to the P.C.S. lab at the Broad Institute of MIT and Harvard and by a grant from the Howard Hughes Medical Institute to P.C.S.

Graphical Abstract

eTOC blurb

Stanton et al. use a directed evolution strategy in mice and macaques to find AAV capsids with increased tropism for the brain after systemic administration. A resulting family of capsids show increased brain transduction and reduced tropism for the liver and other peripheral organs in juvenile macaques compared to AAV9.