GSBS Student Publications

Title

Global CNS transduction of adult mice by intravenously delivered rAAVrh.8 and rAAVrh.10 and nonhuman primates by rAAVrh.10

Student Author(s)

Seemin Seher Ahmed

GSBS Program

Interdisciplinary Graduate Program

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Gene Therapy Center; Department of Microbiology and Physiological Systems; Department of Neurology

Date

7-2014

Document Type

Article

Medical Subject Headings

Animals; Brain; Callithrix; Central Nervous System; Dependovirus; Male; Mice; MicroRNAs; Primates

Disciplines

Genetics | Genetics and Genomics | Molecular Genetics | Nervous System Diseases | Therapeutics | Virology

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.

Rights and Permissions

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

10.1038/mt.2014.68

Related Resources

Link to Article in PubMed

Journal Title

Molecular therapy : the journal of the American Society of Gene Therapy

PubMed ID

24781136