Hereditary
retinal dystrophy is clinically defined as a broad group of chronic and progressive disorders that affect visual function by causing photoreceptor degeneration. Previously, we identified mutations in the gene encoding receptor expression-enhancing
protein 6 (REEP6), in individuals with autosomal recessive
retinitis pigmentosa (RP), the most common form of inherited
retinal dystrophy. One individual was molecularly diagnosed with biallelic REEP6 mutations, a missense mutation over a frameshift mutation. In this study, we generated Reep6 compound heterozygous mice, Reep6L135P/-, which mimic the patient genotype and recapitulate the early-onset
retinal degeneration phenotypes observed in the individual with RP. To determine the feasibility of rescuing the Reep6 mutant phenotype via gene replacement
therapy, we delivered Reep6.1, the mouse retina-specific
isoform of REEP6, to photoreceptors of Reep6 mutant mice on postnatal day 20. Evaluation of the
therapeutic effects 2 months posttreatment showed improvements in the photoresponse as well as preservation of photoreceptor cells. Importantly,
guanylyl cyclase 1 (GC1) expression was also restored to the outer segment
after treatment. Furthermore, rAAV8-Reep6.1 single treatment in Reep6 mutant mice 1 year postinjection showed significant improvements in
retinal function and morphology, suggesting that the treatment is effective even after a prolonged period. Findings from this study show that gene replacement
therapy in the retina with rAAV overexpressing Reep6 is effective, preserving photoreceptor function in Reep6 mutant mice. These findings provide evidence that rAAV8-based gene therapy can prolong survival of photoreceptors in vivo and can be potentially used as a therapeutic modality for treatment of patients with RP.