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Development of a Gene Therapy Vector for RDH12-Associated Retinal Dystrophy

Research output: Contribution to journalArticlepeer-review

Kecia L. Feathers, Lin Jia, Nirosha Dayanthi Perera, Adrienne Chen, Feriel K. Presswalla, Naheed W. Khan, Abigail T. Fahim, Alexander J. Smith, Robin R. Ali, Debra A. Thompson

Original languageEnglish
Pages (from-to)1325-1335
Number of pages11
JournalHuman Gene Therapy
Issue number11
PublishedNov 2019

Bibliographical note

Funding Information: This study was supported by Foundation Fighting Blindness, RDH12 Fund for Sight, Research to Prevent Blindness (chair award), University of Michigan Kellogg Eye Center, NIH Core Grant for Vision Research (P30 EY-07003), Medical Research Council grant MR/J005215/1, the NIHR Biomedical Research Centre based at Moorfields Eye Hospital, NHS Foundation Trust, University College London Institute of Ophthalmology, and RP Fighting Blindness. Publisher Copyright: © Copyright 2019, Mary Ann Liebert, Inc., publishers 2019. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

King's Authors


Early-onset severe retinal dystrophy (EOSRD) is a genetically heterogeneous group of diseases resulting in serious visual disability in children. A significant number of EOSRD cases, often diagnosed as Leber congenital amaurosis (LCA13), are associated with mutations in the gene encoding retinol dehydrogenase 12 (RDH12). RDH12 is a member of the enzyme family of short-chain dehydrogenases/reductases. In the retina, RDH12 plays a critical role in reducing toxic retinaldehydes generated by visual cycle activity that is required for the light response of the photoreceptor cells. Individuals with RDH12 deficiency exhibit widespread retinal degeneration impacting both rods and cones. Although Rdh12-deficient (Rdh12-/-) mice do not exhibit retinal degeneration, functional deficits relevant to visual cycle function can be demonstrated. In the present study, we describe the development and preclinical testing of a recombinant adeno-associated viral (rAAV) vector that has the potential for use in treating EOSRD due to RDH12 mutations. Wild-type and Rdh12-/- mice that received a subretinal injection of rAAV2/5 carrying a human RDH12 cDNA driven by a human rhodopsin-kinase promoter exhibited transgene expression that was stable, correctly localized, and did not cause retinal toxicity. In addition, administration of the vector reconstituted retinal reductase activity in the retinas of Rdh12-/- mice and decreased susceptibility to light damage associated with Rdh12 deficiency, thus demonstrating potential therapeutic efficacy in an animal model that does not exhibit a retinal degeneration phenotype. These findings support further efforts to develop gene replacement therapy for individuals with RDH12 mutations.

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