Abstract
Purpose :
The dry form of age related macular degeneration (AMD) is characterized by subretinal deposits resulting in photoreceptor damage, similar to what is observed in Stargardt Disease, a juvenile form of dry AMD. Our prior studies showed that the broad spectrum modifier, Nuclear Receptor Subfamily 2 Group E Member 3 (NR2E3), rescues retinal degeneration in several mouse models and regulates similar gene networks as retinoic acid related orphan receptor α (RORA). Here, we performed a translational study evaluating the efficacy of RORA to ameliorate retinal degeneration in ATP Binding Cassette Subfamily A Member 4 (ABCA4) knockout mice (Abca4-/-) mice, an experimental model of Stargardt Disease.
Methods :
This study was carried out in accordance with the Association for Research in Vision and Ophthalmology (ARVO) Statement for the Use of Animals in Ophthalmic and Vision Research. 1 month (1M) male and female Abca4-/- mice were subretinally injected with human RORA contained in an AAV5 vector (AAV5hRORA), (n≥5), followed by fundus blue autofluorescence (BAF) imaging, electroretinography (ERG) and immunohistochemistry (IHC) for CD59, an inhibitor of the membrane attack complex (MAC) implicated in AMD.
Results :
BAF imaging showed a reduction in AF levels of 2M, 4M and 7M treated Abca4-/- eyes compared with untreated eyes. Similarly, Abca4-/- treated eyes had a higher scotopic b-wave amplitude at 2M (n=8) compared with untreated eyes. Abca4-/- mice also showed a greater percent recovery of the scotopic a-wave amplitude after photobleaching at 4M and 10M. Immunohistochemical analysis revealed increased expression of CD59 in Abca4-/- treated eyes compared to untreated eyes at 3M and 6M.
Conclusions :
This is the first study evaluating the impact of RORA as a modifier gene therapy to ameliorate retinal degeneration. Our studies show efficacy of RORA in improving the dry AMD-like pathology and function in Abca4-/- mice. The increased expression of CD59 in treated Abca4-/- eyes suggests that the molecular mechanism by which RORA ameliorates Abca4-/- degeneration is by modifying expression of gene networks perturbed in AMD.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.