New therapeutic strategies for treating blindness in Wolfram syndrome

Wolfram syndrome 1 (WS1) is a rare and multisystemic genetic disease. In most cases, the first clinical sign is the development of non-autoimmune diabetes mellitus during infancy, followed by optic atrophy, which leads to progressive visual loss in adolescence, progressing relentlessly to blindness in adulthood. While diabetic symptoms are clinically treatable with anti-diabetic therapies, therapies to arrest or delay the loss of sight are currently lacking. Optic atrophy is caused by the selective loss of retinal ganglion cells (RGCs) and their axons in the optic nerve, with a pattern of degeneration that mainly affects the central part of the optic tract rather than the periphery, and is accompanied by varying degrees of demyelination. The gene mutated in WS1 is WFS1, which encodes for Wolframin, a multi-transmembrane protein resident in the endoplasmic reticulum. We have recently showed that RGC degeneration is triggered by dysfunctions in the surrounding glial cells, impairing the transfer of energy molecules necessary for the survival and function of RGCs. Based on this new knowledge, we have conceived two novel therapeutic approaches to test in Wolfram mutant mice. In the former we will exploit new dietary formulations conceived to boost energetic metabolism in RGCs, thus promoting their function and survival. In the latter, we have designed different viral gene replacement strategies to re-express a Wfs1 functional Wfs1 gene copy in various retinal cells, to define an optimal approach for cell-type-specific reactivation of Wfs1 gene function in order to protect and mitigate vision loss in WS1.