SPVN06, a Novel Mutation-Independent AAV-based Gene Therapy, Protects Cone Degeneration in a Pig Model of Retinitis Pigmentosa

Abstract

Purpose : Rod-Cone dystrophies (RCD) are inherited neurodegenerative diseases characterized by an initial loss of rod photoreceptors (rods) followed by loss of cone photoreceptors (cones) eventually causing blindness. Over 1.5 million people worldwide are affected by RCD with ~65 genes identified. The NXNL1 gene encodes two proteins produced by rods, rod-derived cone viability factor (RdCVF) and its full-length isoform, thioredoxin RdCVFL, also expressed by cones, that support cone survival by promoting glycolysis and preventing oxidative damage, respectively. Delivery of RdCVF/L via adeno associated viral (AAV) vectors to the retina promote cone survival in RCD mouse models (Byrne et al., 2015, J. Clin. Invest.). We delivered SPVN06, a novel mutation-independent AAV-based drug candidate encoding both human RdCVF and RdCVFL sequences, in a large animal model of autosomal dominant retinitis pigmentosa (adRP), the transgenic P23H human rhodopsin (TgP23H hRho) pig, and evaluated cone survival.

Methods : Eight neonatal TgP23H hRho pigs received a unilateral subretinal injection of SPVN06 at 6.1E10 vg/eye (50 µL). We conducted regular ocular exams and fundus imaging to assess tolerability and retinal structure. Animals were euthanized 3 (n=4) or 6 months (n=4) post injection. Retinas were collected and processed for immunohistochemistry. Morphological differences in SPVN06-treated retinas vs control fellow eyes were assessed in the four animals euthanized 3 months post injection. Morphological analysis of 6 months post injection retinas are currently underway.

Results : Subretinal administration of SPVN06 is well tolerated. In three of the four animals, cone morphology is better preserved compared to the same area in the fellow, control eye within the area of treatment. Among those three animals, treated cones have significantly longer inner and outer segments (39%; p<0.05), and significantly more cones express medium-wavelength opsin (m-opsin; 90%).

Conclusions : In the TgP23H hRho model of human adRP, SPVN06 subretinal administration is well tolerated and preserves cone morphology and m-opsin expression. SPVN06 is expected to protect against cone degeneration in RCD patients independent of the causative mutation.

This is a 2021 ARVO Annual Meeting abstract.