A Designer AAV Variant Permits Efficient Retrograde Access to Projection Neurons

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...

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Published in:Neuron (Cambridge, Mass.) Mass.), 2016-10, Vol.92 (2), p.372-382
Main Authors: Tervo, D. Gowanlock R., Hwang, Bum-Yeol, Viswanathan, Sarada, Gaj, Thomas, Lavzin, Maria, Ritola, Kimberly D., Lindo, Sarah, Michael, Susan, Kuleshova, Elena, Ojala, David, Huang, Cheng-Chiu, Gerfen, Charles R., Schiller, Jackie, Dudman, Joshua T., Hantman, Adam W., Looger, Loren L., Schaffer, David V., Karpova, Alla Y.
Format: Article
Language:English
Subjects:
Animals
Brain research
Capsid
Cerebellum - cytology
Cerebellum - metabolism
Dependovirus
Editing
Evolution
Experiments
Female
Gene Editing - methods
Gene therapy
Gene Transfer Techniques
Genetic Vectors
Genomes
Male
Mice
Nervous system
Neurons
Neurons - metabolism
Rats
Regulatory approval
Viruses
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Summary: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. [Display omitted] •AAV can be endowed with robust retrograde functionality through directed evolution•Up to two orders of magnitude increase in retrograde transport over existing variants•Efficiency comparable to synthetic tracers•Sufficient payload expression for circuit interrogation and gene manipulation Projection neurons are a critical component of large-scale networks distributing the results of local circuit computations between distant brain regions, but their specific contribution is often hard to pinpoint because of the difficulty of gaining selective genetic access. Tervo et al. introduce a designer variant of adeno-associated virus, rAAV2-retro, that allows for efficient mapping, monitoring, and manipulation of projection neurons.
ISSN:0896-6273
1097-4199
DOI:10.1016/j.neuron.2016.09.021