Niemann Pick Type C (NPC) is a rare neurodegenerative lipidosis that is characterized by lipid storage in the endosomalflysosomal system. Current treatment modalities for this devastating disease are currently non-existent due to the severe obstacles associated with accessing the central nervous system with proteins or genes. The majority of mutations causing NPC disease are missense mutations. Studies have shown that some of these mutations, including the most prevalent ho61T allele, result in the production of proteins that may be functional but are targeted for degradation due to misfolding. Furthermore, we and others have observed that overexpression of the mutant proteins can rescue the disease phenotype, suggesting that upregulation of the endogenous NPC1 mutant protein is a new drug treatment modality for the disorder. We hypothesize that small chemical molecules that can increase the expression of NPC1 can be identified and thus propose the following specific aims: 1) High throughput screening for identification of small molecules that upregulate NPC1 expression, utilizing the MLSCN (Molecular Libraries Screening Center Network) compound collection for drug-like small chemical molecules, and 2) Characterize and confirm positive hits, using in vitro assays, for their therapeutic potential in the treatment of NPC1 disease. These studies will result in the identification of candidate compounds that will ultimately be evaluated in vivo in an NPC mouse model to determine their therapeutic potential and future drug development.
Diseases that affect the brain are currently difficult if not impossible to treat. We have developed a novel approach to treat devastating genetic diseases with neurological involvement that are currently untreatable by utilizing molecules that can upregulate the expression of the mutant protein providing partial correction of the disease phenotype.
