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Published July 2014 | Supplemental Material
Journal Article Open

Global CNS Transduction of Adult Mice by Intravenously Delivered rAAVrh.8 and rAAVrh.10 and Nonhuman Primates by rAAVrh.10

Abstract

Some recombinant adeno-associated viruses (rAAVs) can cross the neonatal blood-brain barrier (BBB) and efficiently transduce cells of the central nervous system (CNS). However, in the adult CNS, transduction levels by systemically delivered rAAVs are significantly reduced, limiting their potential for CNS gene therapy. Here, we characterized 12 different rAAVEGFPs in the adult mouse CNS following intravenous delivery. We show that the capability of crossing the adult BBB and achieving widespread CNS transduction is a common character of AAV serotypes tested. Of note, rAAVrh.8 is the leading vector for robust global transduction of glial and neuronal cell types in regions of clinical importance such as cortex, caudate-putamen, hippocampus, corpus callosum and substantia nigra. It also displays reduced peripheral tissue tropism compared to other leading vectors. Additionally, we evaluated rAAVrh.10 with and without microRNA (miRNA)-regulated expressional detargeting from peripheral tissues for systemic gene delivery to the CNS in marmosets. Our results indicate that rAAVrh.8, along with rh.10 and 9, hold the best promise for developing novel therapeutic strategies to treat neurological diseases in the adult patient population. Additionally, systemically delivered rAAVrh.10 can transduce the CNS efficiently and its transgene expression can be limited in the periphery by endogenous miRNAs in adult marmosets.

Additional Information

© 2014 American Society of Gene & Cell Therapy. All rights reserved. Received 22 November 2013; accepted 15 April 2014; Accepted article preview online 30 April 2014. We thank Dr. Hong Cao for assisting with confocal imaging and Ms. Sili Zhou for animal care. This work was supported by grants from NIH/NINDS (RO1NS059708), the ALS Association, ALS Therapeutic Alliance and the Packard Center for ALS Research at Johns Hopkins to Z.X. The study was also funded by an internal grant from University of Massachusetts, grants from Jacob's Cure, NTSAD Foundation, and Canavan Foundation and National Institutes of Health R01 grant (1R01NS076991) to G.G., and partially supported by a grant from National High Technology Research and Development Programm ("863" Program) of China (2012AA020810) to G.G. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. G.G is a founder of Voyager Therapeutics and holds equity in the company. G.G is an inventor on patents with potential royalties licensed to Voyager Therapeutics.

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Supplemental Material - mt201468x9.zip

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