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 Charles Desrosiers, Robert Brown, Zuoshang Xu, Guangping Gao

Research output: Contribution to journalArticle

92 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1299-1309
Number of pages11
JournalMolecular Therapy
Volume22
Issue number7
DOIs
StatePublished - 2014
Externally publishedYes

Fingerprint

Primates
Central Nervous System
Callithrix
Dependovirus
Blood-Brain Barrier
MicroRNAs
Tropism
Corpus Callosum
Putamen
Substantia Nigra
Transgenes
Neuroglia
Genetic Therapy
Hippocampus
Population
Genes

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology
  • Medicine(all)

Cite this

Global CNS transduction of adult mice by intravenously delivered rAAVrh.8 and rAAVrh.10 and nonhuman primates by rAAVrh.10. / 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 Charles; Brown, Robert; Xu, Zuoshang; Gao, Guangping.

In: Molecular Therapy, Vol. 22, No. 7, 2014, p. 1299-1309.

Research output: Contribution to journalArticle

Yang, B, Li, S, Wang, H, Guo, Y, Gessler, DJ, Cao, C, Su, Q, Kramer, J, Zhong, L, Ahmed, SS, Zhang, H, He, R, Desrosiers, RC, Brown, R, Xu, Z & Gao, G 2014, 'Global CNS transduction of adult mice by intravenously delivered rAAVrh.8 and rAAVrh.10 and nonhuman primates by rAAVrh.10', Molecular Therapy, vol. 22, no. 7, pp. 1299-1309. https://doi.org/10.1038/mt.2014.68
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 Charles ; Brown, Robert ; Xu, Zuoshang ; Gao, Guangping. / Global CNS transduction of adult mice by intravenously delivered rAAVrh.8 and rAAVrh.10 and nonhuman primates by rAAVrh.10. In: Molecular Therapy. 2014 ; Vol. 22, No. 7. pp. 1299-1309.
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