Lysosomal storage disorders are fatal genetic diseases caused by defects in a wide range of proteins associated with the endosomal-lysosomal system. Niemann-Pick type C (NPC) disease is a cholesterol- glycosphingolipid (GSL) storage disorder caused most commonly by defects in NPC1, a transmembrane protein believed critical in retroendocytic trafficking of substrates from lysosomes, and in NPG2, a soluble lysosome protein of unknown function. Absence of either protein causes an essentially identical condition with affected children exhibiting progressive neurological decline beginning at 4-6 years of age and with death occurring in the second decade of life. An important observation in terms of therapy is that affected children most often appear normal at birth and only later, after a threshold of intracellular storage and metabolic disruption has been exceeded, do clinical symptoms develop. This important feature indicates that there is a window of opportunity after birth when therapy aimed at correction of the metabolic defect could potentially rescue cells from their disease fate and thereby ameliorate or prevent brain dysfunction. Therapeutic options for NPC disease, however, are very limited, with enzyme replacement and cell-mediated therapies providing little hope of benefit, particularly for NPC1 deficiency since this protein is not secreted by cells. Even gene therapy will likely only be beneficial to transduced cells again due to the lack of transfer of the NPC1 protein between cells. These clear limitations have driven development of a new therapeutic option - drugs that can limit the build-up of offending substrates in brain and other organs - known as substrate reduction therapy (SRT). An initial approach here was a small molecule inhibitor of GSL synthesis (N-butyldeoxnorjirimycin, Zavesca(r)) which we pioneered as a therapy for NPC disease. A more recent finding suggests that a naturally occurring compound, the cholesterol-derived neurosteroid known as allopregnanolone (ALLO), has a similar ability to limit lysosomal storage in NPC disease. While the mechanism by which ALLO is able to achieve this effect is unknown, recent findings suggest a critical feature is its ability to act as a ligand for the pregnane X receptor (PXR) and thereby to exert transcriptional control over numerous genes, including those controlling sterol synthesis. The overall goals of our study are to optimize the administration and efficacy of SRT agents using the NPC mouse models, to test an expanded number of candidate PXR-ligand compounds and determine their effects, on cholesterol and GSL accumulation, and to determine whether the-use of SRT agents in combination will lead to even greater efficacy in delaying and/or preventing clinical deterioration in NPC disease. In addition to testing therapies of direct and practical relevance to NPC-affected children, these studies will also further explore the linkage between storage of GSLs and cholesterol in NPC disease and their relationship to NPC1 and NPC2 protein function. ? ? ?
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