Global CNS transduction of adult mice by intravenously delivered rAAVrh.8 and rAAVrh.10 and nonhuman primates by rAAVrh.10
Authors
Yang, BinLi, Shaoyong
Wang, Hongyan
Guo, Yansu
Gessler, Dominic J.
Cao, Chunyan
Su, Qin
Kramer, Joshua
Zhong, Li
Ahmed, Seemin Seher
Zhang, Hongwei
He, Ran
Desrosiers, Ronald C.
Brown, Robert H. Jr.
Xu, Zuoshang
Gao, Guangping
Student Authors
Seemin Seher AhmedUMass Chan Affiliations
Department of NeurologyDepartment of Microbiology and Physiological Systems
Gene Therapy Center
Department of Biochemistry and Molecular Pharmacology
Document Type
Journal ArticlePublication Date
2014-07-01Keywords
Animals; Brain; Callithrix; Central Nervous System; Dependovirus; Male; Mice; MicroRNAs; PrimatesGenetics
Genetics and Genomics
Molecular Genetics
Nervous System Diseases
Therapeutics
Virology
Metadata
Show full item recordAbstract
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.Source
Mol Ther. 2014 Jul;22(7):1299-309. doi: 10.1038/mt.2014.68. Epub 2014 Apr 30. Link to article on publisher's siteDOI
10.1038/mt.2014.68Permanent Link to this Item
http://hdl.handle.net/20.500.14038/33352PubMed ID
24781136Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1038/mt.2014.68