Therapeutic approaches to Lysosomal Storage Disorders: the example of Pompe Disease

Lysosomal Storage Disorders (LSDs) are different inherited diseases caused by the deficit of lysosomal or non-lysosomal proteins, resulting in the accumulation of undegraded substrates in lysosomes. Recent studies support the idea that LSDs are associated with a global impairment of the entire endo-lysosomal compartment, specifically of autophagy involved in the principal lysosome-related degradative pathway. However little is known about the mechanisms underlying such dysfunction. Identification of these mechanisms is crucial for the development of precisely targeted therapies for LSDs. In this work I demonstrate that secondary accumulation of cholesterol on lysosomal membranes is the principal molecular mechanism at the basis of lysosomal and autophagosomal dysfunction, as it affects the fusogenic ability of lysosomal membranes. Specifically cholesterol overload affects the distribution and function of SNARE proteins, a protein superfamily involved in fusing vesicular membranes with targeted lysosomal membranes. In addition I propose a novel gene therapy approach for the treatment of Pompe Disease, an LSD characterized by glycogen accumulation. This approach relies on the AAV-mediated over-expression of the TFEB gene, a master regulator for lysosomal-autophagosomal biogenesis that is able to partially rescue the lysosomal glycogen storage by increasing the functionality of the lysosomal-autophagosomal pathway.