The goal of this project is to generate proof-of-principle data on a completely novel therapeutic strategy that is based on the modulation of cellular clearance. This strategy will be tested on lysosomal storage diseases (LSDs), a group of over 50 inherited diseases with a progressive, multisystemic phenotype that mostly affects children. Currently available therapies for LSDs have major limitations. We have discovered a transcription factor, TFEB, that controls the biogenesis and function of lysosomes and autophagosomes (Sardiello et al. Science 2009;Settembre et al. Science, 2011) and we have shown that TFEB overexpression promotes cellular clearance of LSDs (Medina et al. Dev. Cell, 2011). Recently, we demonstrated that mTOR inhibitors promote TFEB nuclear translocation and activity (Settembre et al. EMBO J., 2012). In this project, we will: 1) test the therapeutic potential of inducible TFEB overexpression in a mouse model of Multiple Sulfatase Deficiency (MSD). The high severity and broad spectrum of the phenotype of this mouse model will enable us to test the effects of our therapeutic approach on multiple tissues;2) test the therapeutic efficacy of AAV- mediated gene delivery of TFEB in a murine model of Pompe disease (PD), a disorder that primarily involves muscles and heart. This will allow us to compare the efficacy of a TFEB-based approach with more traditional enzyme replacement and gene replacement therapies. We have already obtained very encouraging preliminary data by viral-mediated TFEB overexpression in cultured myotubes derived from immortalized myoblasts and in vivo in a PD mouse model by intramuscular injection of AAV-TFEB;3) identify chemical compounds that promote TFEB activity. We have developed a high-content screening assay based on TFEB nuclear translocation. Positive hits identified by high-content drug screening will be subject to a panel of in vitro secondary assays and promising compounds will be administered to mouse models of MSD and PD. If successful, the proposed approach will represent a paradigm shift in the treatment of LSDs. Contrary to existing therapies, which are directed towards single disease entities, our approach based on the modulation of cellular clearance, may have an impact on the therapy of many LSDs and of common, late onset neurodegenerative diseases.

Public Health Relevance

Lysosomal storage diseases (LSDs) are a group of approximately 50 inherited disorders characterized by progressive symptoms affecting multiple organs and due to a defective function of the lysosome, the cellular organelle that is dedicated to the degradation and recycling of the products of cellular metabolism. We demonstrated that the TFEB gene controls lysosomal function and, when activated, promotes clearance in cells from LSD patients and in murine models of LSDs. The goal of this project is to provide proof-of-principle evidence for the use of genetic and pharmacological activation TFEB as a new strategy to modulate cellular clearance and to treat LSDs.

National Institute of Health (NIH)
Research Project (R01)
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Study Section
Therapeutic Approaches to Genetic Diseases (TAG)
Program Officer
Morris, Jill A
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Baylor College of Medicine
Anatomy/Cell Biology
Schools of Medicine
United States
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