714. Gene Therapy Rescues Cone Function and Viability in an Rp2 Knockout Mouse Model for X-Linked Retinitis Pigmentosa Over a Wide Dose Range and a Broad Therapeutic Time Window

Retinitis pigmentosa (RP) refers to a diverse group of inherited retinal dystrophies characterized by a progressive loss of photoreceptors, resulting in vision impairment or blindness. The prevalence of the disease is 1 in 3,500 to 4,000 worldwide. X-linked RP (XLRP) accounts for ~15% of all RP cases and is one of the most severe forms of retinal degeneration. About 10% of the total XLRP cases are caused by mutations in the RP2 gene. A recently developed Rp2 knockout (Rp2-KO) mouse model exhibits early onset, progressive cone photoreceptor dysfunction and degeneration, mimicking early cone involvement in patients with RP2 mutations. To develop gene therapy for the disease, we generated and characterized a self-complementary AAV8 vector carrying the human RP2 expression cassette (AAV8-scRK-RP2), and examined its efficacy in the Rp2-KO mice. Our initial results demonstrated successful cone function rescue following subretinal administration of the vector to the mice (ASGCT 2014, poster#122). In the present study, we continued to examine the long term safety and efficacy of the vector using a broader dose range. Four to six week-old Rp2-KO mice received unilateral subretinal injections of the vector with doses ranging from 5×107 to 1×109 vector genomes (vg)/eye. The fellow eyes were injected with vehicle as controls. Retinal function was assessed by electroretinography (ERG) and optomotor test up to 18 months of age. Our results revealed significantly higher amplitude and faster recovery of cone ERG in vector-treated eyes than control eyes in almost all dose groups through the duration of monitoring starting from 4 months of age. In addition, remarkably better visual acuity was observed in the vector-treated eyes at 18 months of age. The treatment also reversed M-opsin mis-localization, restored cone PDE expression and maintained cone viability. Interestingly, this rescue was achieved in the Rp2-KO mice even when treated at 10-month of age, suggesting the potential benefit of the treatment to older patients. Retinal toxicity was only observed in mice receiving the highest vector dose (1×109 vg/eye), as reflected by reduced rod ERG amplitude and thinner photoreceptor layer. We conclude that our RP2 AAV vector can rescue cone function and viability over a wide dose range and a broad therapeutic time window, which paves the way for future clinical studies.