Therapeutic induction of cell clearance to cure Inherited Retinal Dystrophies

Cell clearance, including autophagy and ubiquitin proteasome pathways, is the homeostatic process by 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. These act by reducing pathological accumulation of protein-aggregates in different neurodegenerative disorders; this aggregation, if left untreated is toxic and reduces 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 highly diverse and heterogenous clinical phenotypes; patients may develop visual loss in early childhood, whereas others may remain asymptomatic until mid-adulthood. However, 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 proteins 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-establish normal degradation in a 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 January 2022 until last budget year, calculated based on the size of the research group.