Gene augmentation therapy treats mature mice with complete congenital stationary night blindness (cCSNB), improving retinal function and visual acuity

ABSTRACT Recombinant adeno-associated virus (rAAV) mediated gene therapy is an effective approach for targeting therapeutic genes to retinal photoreceptors. Complete congenital stationary night blindness (cCSNB) is a genetically heterogeneous inherited retinal disease caused by mutations in one of several genes, which are part of a large and interdependent depolarizing bipolar cell (DBC) signalplex required for normal synaptic signaling with photoreceptors. These genes include NYX, GRM6, TRPM1, GPR179 , and LRIT3, and the cCSNB phenotype that results is characterized by abnormal low light vision, myopia, and nystagmus, but does not include retinal degeneration. Because of the non-progressive and recessive nature of cCSNB we investigated the potential of a gene augmentation approach in the mature retina to improve retinal function and visual acuity. We used a mouse model of cCSNB caused by the loss of LRIT3 to evaluate the efficacy of a single subretinal injection of rAAV expressing LRIT3 in either rods or cones, and the extent of restoration of retinal function and visual acuity. We show that gene augmentation by expressing LRIT3 in the rods of mature Lrit3 -/- retinas restores function and scotopic visual acuity, and when expressed on cones, improves both photopic and scotopic visual acuity.