title: A Designer AAV Variant Permits Efficient Retrograde Access to Projection Neurons.
abstract: Efficient retrograde access to projection neurons for the delivery of sensors and effectors constitutes an important and enabling capability for neural circuit dissection. Such an approach would also be useful for gene therapy, including the treatment of neurodegenerative disorders characterized by pathological spread through functionally connected and highly distributed networks. Viral vectors, in particular, are powerful gene delivery vehicles for the nervous system, but all available tools suffer from inefficient retrograde transport or limited clinical potential. To address this need, we applied in vivo directed evolution to engineer potent retrograde functionality into the capsid of adeno-associated virus (AAV), a vector that has shown promise in neuroscience research and the clinic. A newly evolved variant, rAAV2-retro, permits robust retrograde access to projection neurons with efficiency comparable to classical synthetic retrograde tracers and enables sufficient sensor/effector expression for functional circuit interrogation and in vivo genome editing in targeted neuronal populations. VIDEO ABSTRACT.
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
authors.forename: D Gowanlock R
authors.initials: DG
authors.lastname: Tervo
authors.affiliation: Department of Chemical Engineering and Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Bum-Yeol
authors.initials: BY
authors.lastname: Hwang
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
authors.forename: Sarada
authors.initials: S
authors.lastname: Viswanathan
authors.affiliation: Department of Chemical Engineering and Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gaj
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA; Department of Physiology, Technion Medical School, Bat-Galim, Haifa 3525433, Israel.
authors.forename: Maria
authors.initials: M
authors.lastname: Lavzin
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Ritola
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Lindo
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Michael
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA; Institute of Higher Nervous Activity and Neurophysiology of the Russian Academy of Sciences, Moscow 117485, Russia.
authors.forename: Elena
authors.initials: E
authors.lastname: Kuleshova
authors.affiliation: Department of Chemical Engineering and Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: David
authors.initials: D
authors.lastname: Ojala
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
authors.forename: Cheng-Chiu
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA; Laboratory of Systems Neuroscience, National Institute of Mental Health, Bethesda, MD 20892, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Gerfen
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA; Department of Physiology, Technion Medical School, Bat-Galim, Haifa 3525433, Israel.
authors.forename: Jackie
authors.initials: J
authors.lastname: Schiller
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Dudman
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
authors.forename: Adam W
authors.initials: AW
authors.lastname: Hantman
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
authors.forename: Loren L
authors.initials: LL
authors.lastname: Looger
authors.affiliation: Department of Chemical Engineering and Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA. Electronic address: schaffer@berkeley.edu.
authors.forename: David V
authors.initials: DV
authors.lastname: Schaffer
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. Electronic address: alla@janelia.hhmi.org.
authors.forename: Alla Y
authors.initials: AY
authors.lastname: Karpova
mesh_terms: D000818:Animals; D002213:Capsid; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D000229:Dependovirus; D005260:Female; D000072669:Gene Editing / Q000379:methods*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D051381:Rats