Global CNS transduction of adult mice by intravenously delivered rAAVrh.8 and rAAVrh.10 and nonhuman primates by rAAVrh.10
Interdisciplinary Graduate Program
Department of Biochemistry and Molecular Pharmacology; Gene Therapy Center; Department of Microbiology and Physiological Systems; Department of Neurology
Medical Subject Headings
Animals; Brain; Callithrix; Central Nervous System; Dependovirus; Male; Mice; MicroRNAs; Primates
Genetics | Genetics and Genomics | Molecular Genetics | Nervous System Diseases | Therapeutics | Virology
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.
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Citation: Mol Ther. 2014 Jul;22(7):1299-309. doi: 10.1038/mt.2014.68. Epub 2014 Apr 30. Link to article on publisher's site
DOI of Published Version
Molecular therapy : the journal of the American Society of Gene Therapy
Yang, Bin; Li, 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; and Gao, Guangping, "Global CNS transduction of adult mice by intravenously delivered rAAVrh.8 and rAAVrh.10 and nonhuman primates by rAAVrh.10" (2014). GSBS Student Publications. 1878.