Global CNS transduction of adult mice by intravenously delivered rAAVrh.8 and rAAVrh.10 and nonhuman primates by rAAVrh.10.
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.
Department of Biochemistry & Molecular Pharmacology, University of Massachusetts, Worcester, Massachusetts, USA; Division of Biology, California Institute of Technology, Pasadena, California, USA.
Bin
B
Yang
Gene Therapy Center, University of Massachusetts, Worcester, Massachusetts, USA; Department of Microbiology & Physiology Systems, University of Massachusetts, Worcester, Massachusetts, USA.
Shaoyong
S
Li
Department of Biochemistry & Molecular Pharmacology, University of Massachusetts, Worcester, Massachusetts, USA.
Hongyan
H
Wang
Department of Biochemistry & Molecular Pharmacology, University of Massachusetts, Worcester, Massachusetts, USA; Department of Neurology, the Second Hospital of Hebei Medical University, Shijiazhuang, People's Republic of China.
Yansu
Y
Guo
Gene Therapy Center, University of Massachusetts, Worcester, Massachusetts, USA; Department of Microbiology & Physiology Systems, University of Massachusetts, Worcester, Massachusetts, USA; University of Heidelberg, Medical School, Heidelberg, Germany.
Dominic J
DJ
Gessler
Gene Therapy Center, University of Massachusetts, Worcester, Massachusetts, USA; Department of Physiology, Tongji Medical School, Tongji University, Shanghai, People's Republic of China.
Chunyan
C
Cao
Gene Therapy Center, University of Massachusetts, Worcester, Massachusetts, USA.
Qin
Q
Su
New England Primate Research Center and Harvard Medical School, Southborough, Massachusetts, USA.
Joshua
J
Kramer
Gene Therapy Center, University of Massachusetts, Worcester, Massachusetts, USA; Department of Pediatrics, University of Massachusetts, Worcester, Massachusetts, USA.
Li
L
Zhong
Gene Therapy Center, University of Massachusetts, Worcester, Massachusetts, USA; Department of Microbiology & Physiology Systems, University of Massachusetts, Worcester, Massachusetts, USA.
Seemin Seher
SS
Ahmed
Gene Therapy Center, University of Massachusetts, Worcester, Massachusetts, USA; Department of Microbiology & Physiology Systems, University of Massachusetts, Worcester, Massachusetts, USA; Department of Pharmaceutical Sciences, South Dakota State University, Brookings, South Dakota, USA.
Hongwei
H
Zhang
Gene Therapy Center, University of Massachusetts, Worcester, Massachusetts, USA.
Ran
R
He
New England Primate Research Center and Harvard Medical School, Southborough, Massachusetts, USA.
Ronald C
RC
Desrosiers
Department of Neurology, University of Massachusetts, Worcester, Massachusetts, USA.
Robert
R
Brown
Department of Biochemistry & Molecular Pharmacology, University of Massachusetts, Worcester, Massachusetts, USA. Electronic address: zuoshang.xu@umassmed.edu.
Zuoshang
Z
Xu
Gene Therapy Center, University of Massachusetts, Worcester, Massachusetts, USA; Department of Microbiology & Physiology Systems, University of Massachusetts, Worcester, Massachusetts, USA; State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China. Electronic address: guangping.gao@umassmed.edu.
Guangping
G
Gao
D000818:Animals; D001921:Brain / Q000378:metabolism; D002144:Callithrix; D002490:Central Nervous System / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D011323:Primates
D035683:MicroRNAs