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Adeno-associated virus (AAV) vectors are important gene delivery tools for the treatment of many recessively inherited retinal diseases. For example, a wild-type (WT) AAV5 vector can deliver a full-length  Cnga3  (cyclic nucleotide-gated channel alpha-3) cDNA to target cells of the cone photoreceptor function loss 5 ( cpfl5 ) mouse, a spontaneous animal model of achromatopsia with a  Cnga3  mutation. Gene therapy restores cone-mediated function and blocks cone degeneration in the mice. However, since transgene expression delivered by an AAV vector shows relatively short-term effectiveness, this cannot be regarded as a very successful therapy. AAV2 and AAV8 vectors with capsid mutations have significantly enhanced transduction efficiency in retinas compared to WT AAV controls. In this study, AAV8 (Y447, 733F+T494V)-treated  cpfl5  retinas showed greater preservation of short-term cone electroretinogram (ERG) responses than AAV8 (Y447, 733F)- or AAV2 (Y272, 444, 500, 730F+T491V)-mediated treatments. To explore the long-term rescue effect, AAV8 (Y447, 733F+T494V)-treated  cpfl5  retinas were evaluated at 9 months following postnatal day 14 (P14) treatment. Rescued ERG responses in the cones of treated  cpfl5  eyes decreased with increasing age, but still maintained more than 60% of the WT mouse responses at the oldest time point examined. Expression of CNGA3 and M/S-opsins was maintained in cone outer segments of the treated  cpfl5  eyes and was equal to expression in age-matched WT retinas. Near-normal cone-mediated water maze behavior was observed in the treated  cpfl5  mice. As these are the longest follow-up data reported thus far, AAV8 with capsid Y-F and T-V mutations may be one of the most effective AAV vectors for long-term treatment in a naturally occurring mouse model of CNGA3 achromatopsia.

Long-term retinal cone rescue using a capsid mutant AAV8 vector in a mouse model of CNGA3-achromatopsia