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Gene therapy using adeno-associated viral (AAV) vectors for the treatment of retinal degenerations has shown safety and efficacy in clinical trials. However, very high levels of vector expression may be necessary for the treatment of conditions such as Stargardt disease where a dual vector approach is potentially needed, or in optogenetic strategies for end-stage degeneration in order to achieve maximal light sensitivity. In this study, we assessed two vectors with single capsid mutations, rAAV2/2(Y444F) and rAAV2/8(Y733F) in their ability to transduce retina in the Abca4(-/-) and rd1 mouse models of retinal degeneration. We noted significantly increased photoreceptor transduction using rAAV2/8(Y733F) in the Abca4(-/-) mouse, in contrast to previous work where vectors tested in this model have shown low levels of photoreceptor transduction. Bipolar cell transduction was achieved following subretinal delivery of both vectors in the rd1 mouse, and via intravitreal delivery of rAAV2/2(Y444F). The successful use of rAAV2/8(Y733F) to target bipolar cells was further validated on human tissue using an ex vivo culture system of retinal explants. Capsid mutant AAV vectors transduce human retinal cells and may be particularly suited to treat retinal degenerations in which high levels of transgene expression are required.

Original publication

DOI

10.1038/gt.2016.54

Type

Journal article

Journal

Gene Ther

Publication Date

11/2016

Volume

23

Pages

767 - 774

Keywords

ATP-Binding Cassette Transporters, Animals, Capsid Proteins, Cell Line, Tumor, Dependovirus, Genetic Therapy, Genetic Vectors, Humans, Intravitreal Injections, Mice, Mice, Inbred C57BL, Mutation, Missense, Photoreceptor Cells, Retinal Degeneration