AAV Gene Augmentation Therapy Rescues the Phenotype in the RDH5-/- Cat Model of Fundus Albipunctatus.

PURPOSE: Retinol dehydrogenase 5 (RDH5) catalyzes the final oxidation for visual pigment regeneration of 11-cis-retinal as part of the visual cycle in the retinal pigment epithelium (RPE). In humans, RDH5 mutations cause fundus albipunctatus characterized by night blindness, accumulation of white-yellowish fundus spots, and, in a subset of patients, macular degeneration. Currently, there is an unmet need for therapies for patients with RDH5 mutations. Using a large-animal cat model of RDH5-associated disease (RDH5-/-), this study aimed to meet these needs through development of a gene augmentation therapy able to rescue RDH5-associated retinopathies.

METHODS: An adeno-associated virus serotype 2 with triple capsid mutations vector packaged with feline RDH5 cDNA (AAV-VMD2-fRDH5) was subretinally injected into 12 RDH5-/- cats. To assess expression and the impact of treatment on retinal function and structure, immunohistochemistry, high-performance liquid chromatography, rod and cone electroretinograms, spectral-domain optical coherence tomography, and semi-thin resin-embedded sectioning were performed.

RESULTS: The expression of the RDH5 transgene improved rod and cone photoreceptor functional recovery following light exposure and shows promise in slowing/halting area centralis (analogous to the human macula) degeneration.

CONCLUSIONS: This gene augmentation therapy is a promising approach for the treatment of RDH5-associated retinopathies.