Small Molecule-Based Therapies with for Lysosomal Storage Diseases

The general aim of the project is to identify novel therapies for lysosomal storage diseases (LSDs), a group of genetic disorders due to the deficiency of enzymes involved in the degradation and disposal of substrates produced by cells. LSDs in many instances cause progressive physical and neurologic handicap. Several therapeutic strategies have been proposed so far to treat these diseases, but in most cases they have limitations, leave important issues unsolved and have a heavy impact on the quality of life of patients. We plan to test novel approaches, based on the use of drugs (so-called "small molecules") that may have advantages compared with existing therapies, such as a better distribution in the body and the possibility to be taken orally. We will test these new approaches in three of the most frequent LSDs, Pompe disease (PD), a severe and progressive muscle disease, Fabry disease (FD), a multisystem disease involving kidney, skin, heart and other organs, and mucopolysaccharidosis IIIA (MPSIIIA), a disease that causes progressive dementia. The strategies that we will use are aimed at enhancing the efficacy of enzyme replacement therapy, a therapeutic approach that is currently in use for several LSDs, or at reducing the rate of substrate synthesis and restoring the equilibrium between substrate synthesis and degradation.