Gene Therapy Rescues Retinal Degeneration in Receptor Expression-Enhancing Protein 6 Mutant Mice.

TitleGene Therapy Rescues Retinal Degeneration in Receptor Expression-Enhancing Protein 6 Mutant Mice.
Publication TypeJournal Article
Year of Publication2019
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 Published2019 Mar
KeywordsAnimals, Dependovirus, Disease Models, Animal, Electrophysiological Phenomena, Electroretinography, Endoplasmic Reticulum Stress, Eye Proteins, Gene Expression, Genetic Therapy, Genetic Vectors, Genotype, Guanylate Cyclase, Immunohistochemistry, Light, Membrane Proteins, Mice, Mice, Knockout, Mutation, Photoreceptor Cells, Protein Transport, Receptors, Cell Surface, Retinal Degeneration, Transduction, Genetic, Transgenes

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, Reep6, 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.

Alternate JournalHum Gene Ther
PubMed ID30101608
PubMed Central IDPMC6437630
Grant ListR01 EY020540 / EY / NEI NIH HHS / United States
P30 CA125123 / CA / NCI NIH HHS / United States
S10 OD023469 / OD / NIH HHS / United States
R01 EY022356 / EY / NEI NIH HHS / United States
P30 EY002520 / EY / NEI NIH HHS / United States
R01 EY018571 / EY / NEI NIH HHS / United States
T32 GM008307 / GM / NIGMS NIH HHS / United States
T32 EY007102 / EY / NEI NIH HHS / United States

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