Project description
Restoration of lysosomal function for the treatment of lysosomal storage diseases
Lysosomal storage diseases (LSDs) are a group of rare genetic metabolic disorders with defects in lysosomal function and a consequent block in the degradative function of the cells. The skeleton is the most affected organ, and current therapies are largely ineffective. The EU-funded RE-STORE project will develop a cell-based screening platform to identify selective ER-phagy inducers from the degradation of endoplasmic reticulum fragments via the lysosome/autophagy pathway to target the skeletal phenotype of LSDs and contribute to the development of new therapeutics. The researchers previously demonstrated that degradation of ER fragments by means of ER-phagy is essential for secretion of procollagens. This process is impaired in LSD chondrocytes and osteoblasts, resulting in the skeletal growth retardation observed in LSD mouse models.
Objective
Lysosomal storage disorders (LSDs) are a family of inherited genetic diseases characterized by lysosomal dysfunction, with a consequent block in the degradative capacity of the cell. The skeleton is one of the most affected organs in LSD patients and current therapies are largely ineffective for the treatment of bone and cartilage manifestations. Thanks to the support of the ERC-starting grant BONEPHAGY we demonstrated that the degradation of the endoplasmic reticulum fragments via lysosome/autophagy pathway (ER-phagy) exerts ER quality control functions that are essential for secretion of procollagens. This process is impaired in LSD chondrocytes and osteoblasts, the cartilage and bone forming cells, respectively and accounts, at least in part, for the skeletal growth retardation observed in LSD mouse models. Prompted by these exciting findings, RE-STORE proposes to develop a novel cell-based integrated screening platform to identify selective ER-phagy inducers to target the skeletal phenotype of LSDs and contribute significantly to their development into innovative therapeutics. The access to proprietary library, through a collaboration with an industrial partner, and the set-up of a rapid hit confirmation in disease animal models will allow RE-STORE to establish a complete drug development pipeline for the selected hits. RE-STORE is an ambitious project that aims to develop an innovative substrate-to-lysosome screening approach for the study of selective autophagy and to identify new therapies for the so-called “ER-storage disorders” characterized by accumulation of misfolded polypeptides in the lumen of the ER.
Programme(s)
Funding Scheme
ERC-POC - Proof of Concept GrantHost institution
00185 Roma
Italy