Therapeutic restoration of synaptic architecture, retinal and visual function, and prevention of retinal degeneration in a mouse model of retinal dystrophy

Vision depends on the transfer of photoreceptor signals through the retina and then to many CNS visual nuclei. While the most common inherited retinal diseases (IRDs) involve defects in rod and/or cone function, another group (referred to as congenital stationary night blindness (CSNB)) results from defects in glutamate release from photoreceptors, or conversion of the glutamatergic signal in bipolar cells. One example results from mutations in the CACNA2D4 gene, which encodes a subunit of the voltage-gated calcium channel that is critical for glutamate release from both rod and cone photoreceptors. Mutations in CACNA2D4 result in a range of phenotypes in human patients, from incomplete CSNB to rod-cone dystrophy. In the CACNA2D4 knockout mouse ( α2δ4 ^-/- ), there is slow photoreceptor degeneration, the photoreceptor-to-bipolar cell synapse is disorganized, and the retina lacks scotopic and photopic full-field electroretinogram b-waves; this also results in low visual acuity. Using adult α2δ4 ^-/- mice, we show that recombinant adeno-associated virus (rAAV)-mediated gene therapy directed to rod photoreceptors prevents rod degeneration, restores synaptic organization, retinal function, and improves visual acuity under both light- and dark-adapted conditions. This rescue was maintained for up to 14 months post-treatment. Together, our results demonstrate that synaptic structure and function can be restored in the mature mouse retina in a model of complete synaptic disorganization. The results highlight the neuroprotective potential of targeting synaptic organizing proteins in retinal gene therapy.