Preclinical safety and biodistribution of SPVN06, a novel gene- and mutation-independent gene therapy for rod-cone dystrophies

Abstract Rod-cone dystrophies (RCD) are caused by mutations in over 100 genes associated with photoreceptor function, leading to progressive and sequential loss of rod and cone photoreceptors. These mutations generally disrupt retinal metabolism and oxidative stress response accelerating disease progression and vision loss. SPVN06 is an adeno-associated virus (AAV)-based gene- and mutation-agnostic investigational therapy designed to slow cone degeneration by delivering long-term expression of rod-derived cone viability factor (RdCVF) and its full-length isoform, thioredoxin RdCVFL, following a single subretinal administration. These proteins support cone survival by promoting glucose metabolism and reducing oxidative damage, respectively, providing a gene and mutation independent therapeutic approach for RCD. SPVN06 IND-enabling program included pharmacology evaluation in the rd10/rd10 mouse model of RCD (1.0 × 10 8 vector genomes (vg)/eye up to 1 month) along with systemic and ocular safety and biodistribution evaluation in non-human primates (NHPs, 6.0 × 10 9 to 3.0 × 10 11 vg/eye up to 3 months). In the rd10/rd10 mice, SPVN06 showed preserved vision, as assessed by optokinetic tracking. In NHPs, SPVN06 was well-tolerated up to 6.0 × 10 10 vg/eye, with high and stable RdCVF and RdCVFL mRNA expression levels in the retina and retinal pigment epithelium. These results supported the initiation of the ongoing Phase I/II PRODYGY trial with RCD (NCT05748873).