Identification of molecular targets for the treatment of the skeletal phenotype in Lysosomal Storage Disorders

Lysosomal storage diseases (LSDs) are inherited disorders affecting 1/5000 people. The symptoms of LSDs are progressive and, depending on the particular disorder, can be mild to severe, affecting several tissues and organs, including brain and bones. In about 50% of them the skeleton is one of the most affected organ. The lysosome is the "recycling center" of each cell, breaking down unwanted material into simple products for the cell to use to build new material. This function is achieved through the concerted action of enzymes involved in the stepwise degradation of the substrates. Therefore, LSDs are characterized by the accumulation of storage material, due to defective lysosomal degradation and impaired cellular clearance. There are no effective cures for LSDs, in particular for the neurologic and bone abnormalities. Currently the only therapy for the treatment of LSDs is the "enzyme replacement therapy". The enzyme that is missing in the body is introduced into the blood stream and is uptaken by the cells that can then start to degrade the accumulated substance. However, the cells that compose the skeleton do not uptake efficiently the enzyme, and thus the skeleton does not respond to the therapy. In this project we propose alternative strategies for the treatment of the skleletal manifestations in LSDs. This project aims at providing proof-of-principle studies in vivo to promote cellular clearance as a new strategy to treat LSDs.