Clérin E
Institut de la Vision, France
Title: The development of a therapy for retinitis pigmentosa based on the nucleoredoxin-like 1 gene
Biography
Biography: Clérin E
Abstract
Retinitis pigmentosa is an inherited retinal degeneration that processes from the death of rods followed by dysfunction and degeneration of cones. The nucleoredoxin-like 1 (NXNL1) gene encodes for two different proteins: the trophic factor rod-derived cone viability factor (RdCVF) and the long form, the thioredoxin (RdCVFL). RdCVF acts by stimulating aerobic glycolysis to sustain the outer cone segment renewal and RdCVFL protects the cones against hyperoxia. To translate this promising therapy towards the clinic, independently of the causative gene, we have evaluated the therapeutic benefit of delivering both products of the NXNL1 gene by subretinal injection with an AAV vector targeting retinal pigmented epithelial cells and cones in a mouse model of the disease. Unilateral subretinal delivery of AAV-RdCVF/RdCVFL as compared to AAV-GFP and sham were performed in rd10 mice at 15 days post-natal. The visual acuity test was carried out from 30 days to 55 days post-natal. Eye of animals were collected and used for automated counting after the labelling of cones. The quality control of AAV particles was made by transmission electron microscopy. The kinetics of the loss of visual acuity was significantly retarded statistically after injection of AAV-RdCVF-RdCVFL in three independent experiments. The results were validated by the increase of cone density. We have validated the quality of the viral productions by measuring the percentage of full to empty particles using electron microscopy. Poly-unsaturated fatty acids lipids of the external segment of photoreceptors are essential for phototransduction, prone to oxidation. We show a reduced amount of malondialdehyde (MDA), a marker of lipid peroxidation, for animals injected with AAV-RdCVF-RdCVFL demonstrating the additional protective effect of RdCVFL on cones, strengthening the interest to combine RdCVF and RdCVFL. Our results demonstrate that this treatment will likely be successful in preserving central vision in patients suffering from retinitis pigmentosa in the near future.