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

Yang, Bin and Li, Shaoyong and Wang, Hongyan and Guo, Yansu and Gessler, Dominic J. and Cao, Chunyan and Su, Qin and Kramer, Joshua and Zhong, Li and Seher Ahmed, Seemin and Zhang, Hongwei and He, Ran and Desrosiers, Ronald C. and Brown, Robert and Xu, Zhuoshang and Gao, Guangping (2014) Global CNS Transduction of Adult Mice by Intravenously Delivered rAAVrh.8 and rAAVrh.10 and Nonhuman Primates by rAAVrh.10. Molecular Therapy, 22 (7). pp. 1299-1309. ISSN 1525-0016. PMCID PMC4089005. https://resolver.caltech.edu/CaltechAUTHORS:20140506-144746804

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1038/mt.2014.68DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089005/PubMed CentralArticle
http://www.nature.com/mt/journal/v22/n7/abs/mt201468a.htmlPublisherArticle
http://www.nature.com/mt/journal/v22/n7/suppinfo/mt201468s1.html?url=/mt/journal/v22/n7/abs/mt201468a.htmlRelated ItemSupplementary Information
Alternate Title:I.V. gene transfer to CNS of adult mice and NHPs
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.
Funders:
Funding AgencyGrant Number
NIHR01NS059708
ALS AssociationUNSPECIFIED
ALS Therapeutic AllianceUNSPECIFIED
Johns Hopkins Packard Center for ALS ResearchUNSPECIFIED
Jacob’s CureUNSPECIFIED
NTSAD FoundationUNSPECIFIED
NIH1R01NS076991
National High Technology Research and Development Programm (“863” Program) of China2012AA020810
Canavan FoundationUNSPECIFIED
Subject Keywords:Central nervous system, blood-brain barrier, rAAV vector, neurodegenerative diseases, gene therapy
Issue or Number:7
PubMed Central ID:PMC4089005
Record Number:CaltechAUTHORS:20140506-144746804
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20140506-144746804
Official Citation:Global CNS Transduction of Adult Mice by Intravenously Delivered rAAVrh.8 and rAAVrh.10 and Nonhuman Primates by rAAVrh.10 Bin Yang, Shaoyong Li, Hongyan Wang, Yansu Guo, Dominic J Gessler, Chunyan Cao, Qin Su, Joshua Kramer, Li Zhong, Seemin Seher Ahmed, Hongwei Zhang, Ran He, Ronald C Desrosiers, Robert Brown, Zuoshang Xu and Guangping Gao Mol Ther 22: 1299-1309; advance online publication, June 24, 2014; doi:10.1038/mt.2014.68
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:45541
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:07 May 2014 16:25
Last Modified:03 Oct 2019 06:32

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