Chemical modulation of lysosomal storage in vivo

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DESCRIPTION (provided by applicant): Lysosomal storage diseases are a group of multisystem disorders characterized by the common pathology of abnormal accumulation of storage material in lysosomes. Lysosomal storage diseases often affect the central nervous system and cause significant neurological morbidity. Central nervous system manifestations have been particularly difficult to treat with currently available therapies. We propose here to screen directly for central nervous system-penetrant molecules that reduce abnormal lysosomal storage. We have previously characterized Drosophila lacking the lysosomal enzyme cathepsin D and have shown that they represent a robust model of the abnormal lysosomal storage characteristic of neuronal ceroid lipofuscinosis cause by mutations in the cathepsin D gene in patients and in ovine and murine models. We now propose carrying out an in vivo drug screen in our model to identify small molecules that can reduce or eliminate abnormal lysosomal storage material. Molecules emerging from our screen will not only have the ability to modulate lysosomal function in a fashion that promotes clearance of stored material, but will also have the ability to penetrate a functioning in vivo blood brain barrier. Thus, these drugs will represent attractive therapeutic drug candidates in neuronal lipofuscinoses, and possibly other lysosomal storage diseases as well. These molecules may also provide useful research tools to probe lysosomal function in normal and abnormal physiological conditions. Finally, given the emerging evidence that the autophagosomal/lysosomal system is altered in other neurodegenerative diseases, including Alzheimer's disease, the molecules we identify may also have therapeutic relevance to more common neurodegenerative disorders as well. PUBLIC HEALTH RELEVANCE: Lysosomal storage diseases are devastating disorders that cause severe disability and early death in affected children. We will use a fast, cheap in vivo model system to identify compounds that reduce the lysosomal storage thought to result in death of neuronal death and dysfunction in these diseases. Results from our system will provide important candidate therapeutics and may also help us understand how abnormal neuronal storage leads to cell death.