Therapeutic induction of cell clearance to cure Inherited Retinal Dystrophies

Cell clearance, including autophagy and ubiquitin proteasome pathways, is the homeostatic process through which damaged proteins and organelles are cleared from the cells. Proof-of-concept studies are providing sound evidence for the use of autophagy inducers as therapeutic tools to reduce pathologic accumulation of aggregates in different neurodegenerative disorders in which protein-aggregates are toxic for the neuronal cell lifespan. Our lab uses cellular and animal models to elucidate the physiological roles of autophagy and how its dysfunction may affect RPE/photoreceptor crosstalk in retinal diseases. Inherited retinal dystrophies (IRD) are the most common genetic disorders affecting the eye. They include, among others, Retinitis Pigmentosa, one of the leading causes of inherited blindness, whose incidence is about 1:4,000. These diseases, for which there are currently few disease-modifying therapies, show a great diversity in clinical phenotypes; patients may develop visual loss in early childhood, whereas others may remain asymptomatic until mid-adulthood. They share a common pathological hallmark, death of rod cells, resulting in the development of night blindness with visual field restrictions, accompanied by subsequent loss of cone cells leading to a complete loss of visual fields. Recent advances have pointed out the role of mistrafficking and accumulation of mutated and unfolded protein in impairing normal cellular function and inducing toxicity in both photoreceptor and retinal pigment epithelial cells. Our goal is to identify new therapeutic strategies that enhance autophagy to alleviate pathological protein accumulation and re-establishing normal degradation in mutational independent manner to treat IRD. The "Total Award" amount indicated for this project represents the share of the funding of the Telethon Foundation for research by the Tigem institute from July 2016 until last budget year, calculated based on the size of the research group.