Congratulations to Dr. William Hauswirth on the publication of “AAV2 gene therapy rescues rod photoreceptor functional recovery in the RDH5-mutant cat,” which appeared in the ARVO Annual Meeting Abstract Issue in June.
Abstract
Purpose : Retinol dehydrogenase 5 (RDH5) catalyzes the final oxidation for regeneration of 11-cis-retinal as part of the visual cycle in the retinal pigment epithelium (RPE) needed for regeneration of the visual pigments. In humans, RDH5 mutations cause fundus albipunctatus (FA) which is 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. This study aims to meet this need through development of gene augmentation therapy in a large-animal cat model of RDH5-associated disease. We hypothesize that RDH5 gene augmentation therapy will rescue the functional phenotype of delayed recovery of rod photoreceptor function and delay or prevent degeneration of the macula-equivalent area centralis (AC).
Methods : An adeno-associated virus serotype 2 with triple capsid mutations (AAV2) vector packaged with feline RDH5 cDNA (AAV-VMD2-RDH5) was subretinally injected into five cats with a spontaneously occurring Gly181Val loss-of-function missense variant in RDH5. One eye was injected with the vector, while the other acted as a control. The primary outcome measure was rescue of recovery of rod function following light exposure as assessed by electroretinography (ERG). A secondary outcome measure was prevention of AC degeneration as assessed optical coherence tomography (OCT) and fundus imaging. Following euthanasia, immunohistochemistry was performed to ensure therapy resulted in appropriate expression of the transgene in the RPE.
Results : Gene augmentation therapy (n=5 eyes of 5 cats) resulted in statistically significant improvement in rod functional recovery in the treated vs. untreated eye at one- 3- and 6-months post injection (p-values =0.01, 0.0073 and 0.0052 respectively). Improvement in rod recovery has been maintained up to at least 2-years post-injection. Immunohistochemistry in a 6-month post injection animal showed correct expression of the RDH5 transgene in the RPE of the treated region of the retina.
Conclusions : Gene augmentation improves rod photoreceptor functional recovery following light exposure in RDH5 mutant cats. Animals are being monitored to see if therapy prevents AC degeneration. Gene augmentation is a promising approach for the treatment of RDH5-associated diseases.