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Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems

Chan, Ken Y. and Jang, Min J. and Yoo, Bryan B. and Greenbaum, Alon and Ravi, Namita and Wu, Wei-Li and Sánchez-Guardado, Luis and Lois, Carlos and Mazmanian, Sarkis K. and Deverman, Benjamin E. and Gradinaru, Viviana (2017) Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems. Nature Neuroscience, 20 (8). pp. 1172-1179. ISSN 1097-6256. PMCID PMC5529245.

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Adeno-associated viruses (AAVs) are commonly used for in vivo gene transfer. Nevertheless, AAVs that provide efficient transduction across specific organs or cell populations are needed. Here, we describe AAV-PHP.eB and AAV-PHP.S, capsids that efficiently transduce the central and peripheral nervous systems, respectively. In the adult mouse, intravenous administration of 1 × 1011 vector genomes (vg) of AAV-PHP.eB transduced 69% of cortical and 55% of striatal neurons, while 1 × 1012 vg of AAV-PHP.S transduced 82% of dorsal root ganglion neurons, as well as cardiac and enteric neurons. The efficiency of these vectors facilitates robust cotransduction and stochastic, multicolor labeling for individual cell morphology studies. To support such efforts, we provide methods for labeling a tunable fraction of cells without compromising color diversity. Furthermore, when used with cell-type-specific promoters and enhancers, these AAVs enable efficient and targetable genetic modification of cells throughout the nervous system of transgenic and non-transgenic animals.

Item Type:Article
Related URLs:
URLURL TypeDescription ReadCube access CentralArticle
Chan, Ken Y.0000-0002-8853-5186
Jang, Min J.0000-0002-1536-7177
Greenbaum, Alon0000-0002-2897-876X
Wu, Wei-Li0000-0003-2610-1881
Sánchez-Guardado, Luis0000-0001-5598-8608
Lois, Carlos0000-0002-7305-2317
Mazmanian, Sarkis K.0000-0003-2713-1513
Deverman, Benjamin E.0000-0002-6223-9303
Gradinaru, Viviana0000-0001-5868-348X
Additional Information:© 2017 Macmillan Publishers Limited, part of Springer Nature. Received 13 December 2016; accepted 20 May 2017; published online 26 June 2017. We thank E. Mackey and K. Beadle for assistance with cloning and viral production, P. Anguiano for administrative assistance, and the entire Gradinaru group for discussions. We thank G. Stevens and V. Anand for their efforts in image analysis; P. Rajendran and S. Kalyanam at University of California, Los Angeles and C. Fowlkes at the University of California, Irvine, for discussions, the University of Pennsylvania vector core for the AAV2/9 Rep-Cap plasmid, and M. Brenner at the University of Alabama for the GfABC1D promoter. pAAV-Ef1a-DIO EYFP, pAAV-EF1a-Cre and pAAV-Ef1a-fDIO EYFP were gifts from K. Deisseroth (Addgene plasmids 27056, 55636 and 55641). pEMS2113 and pEMS2115 were gifts from E. Simpson (Addgene plasmids 49138 and 49140). This work was primarily supported by the National Institutes of Health (NIH) through grants to V.G.: Director's New Innovator DP2NS087949 and PECASE; SPARC OT2OD023848-01; National Institute on Aging R01AG047664; BRAIN U01NS090577; and National Institute of Mental Health (NIMH) R21MH103824. Additional funding included the Gordon and Betty Moore Foundation through grant GBMF2809 to the Caltech Programmable Molecular Technology Initiative (to V.G.), the Curci Foundation (to V.G.), the Hereditary Disease Foundation (to V.G. and B.E.D.), the Beckman Institute (to V.G. and B.E.D.) and Rosen Center (to C.L. and V.G.) at Caltech, NIH U01 MH109147 02S1 (to C.L. and V.G.), NIH NS085910 (to S.K.M. and V.G.), the Defense Advanced Research Projects Agency (DARPA) Biological Technologies Office (BTO; to V.G. and B.E.D.) and the Friedreich's Ataxia Research Alliance (FARA) and FARA Australasia (to B.E.D.). S.K.M and V.G. are Heritage Principal Investigators supported by the Heritage Medical Research Institute. Contributions: K.Y.C. and B.E.D. designed and performed experiments, imaged samples and analyzed data. K.Y.C. prepared figures with input from B.E.D. and V.G. M.J.J. analyzed data, prepared figures and assisted with experiments and in manuscript preparation. B.B.Y. assisted with tissue processing, imaging and virus production. A.G. helped with image analysis. N.R. assisted with molecular cloning. W.-L.W. and L.S.-G. assisted in tissue processing. C.L. and S.K.M. assisted in experimental designs. K.Y.C., B.E.D. and V.G. wrote the manuscript with support from all authors. B.E.D. and V.G. conceived the project. V.G. supervised all aspects of the work. Competing financial interests: The California Institute of Technology has filed patent applications related to this work with B.E.D., K.Y.C. and V.G. listed as inventors. B.E.D. and V.G. receive research support from Voyager Therapeutics; this support was not used in preparation of this manuscript or for the studies described therein.
Group:Heritage Medical Research Institute, Tianqiao and Chrissy Chen Institute for Neuroscience
Funding AgencyGrant Number
Gordon and Betty Moore FoundationGBMF2809
Curci FoundationUNSPECIFIED
Hereditary Disease FoundationUNSPECIFIED
Caltech Beckman InstituteUNSPECIFIED
Benjamin M. Rosen Bioengineering CenterUNSPECIFIED
NIHU01 MH109147 02S1
Defense Advanced Research Projects Agency (DARPA)UNSPECIFIED
Friedreich’s Ataxia Research Alliance (FARA)UNSPECIFIED
Heritage Medical Research InstituteUNSPECIFIED
National Institute on AgingUNSPECIFIED
National Institute of Mental Health (NIMH)UNSPECIFIED
Issue or Number:8
PubMed Central ID:PMC5529245
Record Number:CaltechAUTHORS:20170626-152125765
Persistent URL:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:78578
Deposited By: Joy Painter
Deposited On:26 Jun 2017 22:42
Last Modified:09 Mar 2020 13:18

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