Gene Therapy Rescues Retinal Degeneration in Reep6 Mutant Mice.

TitleGene Therapy Rescues Retinal Degeneration in Reep6 Mutant Mice.
Publication TypeJournal Article
Year of Publication2018
AuthorsZaneveld, SAgrawal, Eblimit, A, Liang, Q, Bertrand, R, Wu, N, Liu, H, Nguyen, Q, Zaneveld, J, Wang, K, Li, Y, Chen, R
JournalHum Gene Ther
Date Published2018 Aug 13

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 multiple families with autosomal recessive retinitis pigmentosa (RP), the most common form of inherited retinal dystrophy. One individual was molecularly diagnosed with bi-allelic REEP6 mutations, a missense mutation over a frameshift mutation. In this study, we generated Reep6 compound heterozygous mice, Reep6 L135P/-, which mimic the patient genotype and recapitulate the early onset retinal degeneration phenotypes observed in the RP individual. To determine the feasibility of rescuing Reep6 mutant phenotype via gene replacement therapy, we delivered Reep6.1, the mouse retina-specific isoform of REEP6, to photoreceptors of Reep6 mutant mice at post-natal day 20 (P20). Evaluation of the therapeutic effects 2- months post-treatment showed improvements in the photo-response as well as preservation of photoreceptor cells. Importantly, Guanylyl cyclase 1 (GC1) expression was also restored to the outer segment after treatment. Furthermore, AAV8-Reep6.1 single-treatment in Reep6 mutant mice 1- year post-injection 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 AAV over expressing Reep6 is effective, preserving photoreceptor function in Reep6 mutant mice. These findings provide evidence that AAV8-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.

Alternate JournalHum. Gene Ther.
PubMed ID30101608