Pharmacological restoration of selective autophagy for the treatment of skeletal disorders

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.