Discovery and evaluation of novel therapy for Niemann-Pick type C targeting NPC1

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DESCRIPTION (provided by applicant): Niemann-Pick type C (NPC) disease is a fatal complex lysosomal storage disorder associated with progressive neurodegeneration predominately caused by mutations in NPC1 resulting in accumulation of cholesterol and sphingolipids. Unfortunately, treatment options for NPC disease are still very limited. It was recently reported that histone deacetylase (HDAC) inhibitors can correct cholesterol storage defects in human NPC1 mutant cells, providing a potential basis for novel treatment options for NPC disease. Our lab has shown that the sphingolipid metabolite sphingosine-1-phosphate produced in the nucleus by sphingosine kinase 2 (SphK2) is an endogenous inhibitor of HDAC1/2, linking sphingolipid metabolism to gene expression. In preliminary studies, we found that nuclear SphK2 also phosphorylates FTY720/fingolimod, a drug approved for treatment of multiple sclerosis, and that its active form, FTY720-phosphate, is a potent HDAC1/2 inhibitor that upregulates the cholesterol transporters NPC1 and NPC2. Our objectives are to determine the mechanisms of action of FTY720 and evaluate its therapeutic potential in NPC1 mutant cells and in animal models of NPC. In Aim 1, we will demonstrate that FTY720 corrects cholesterol and sphingolipid storage defects in human NPC1 mutant fibroblasts by inhibition of HDACs leading to increased NPC1 and NPC2 gene expression. In Aim 2, our objective is to establish that administration of FTY720 to NPC1 mutant mice normalizes cholesterol and sphingolipid homeostasis, improves liver function, reduces neuroinflammation, and severity of neurodegeneration, and suppresses disease progression. Our long-term goal is to develop FTY720 as a potential new basis for treatment options for NPC disease. FTY720 has several advantages over HDAC inhibitors as potential treatment for NPC1 disease patients: i. it is an orally bio-available drug; ii. it has already been approved for human use for the treatment of multiple sclerosis; iii. it regulates expression of only a limited number of genes (a majority related to cholesterol and sphingolipid metabolism) compared to other HDAC inhibitors; iv. it has good pharmacokinetics and a long half life; v. it reduces levels of ceramide and sphingolipids; vi. it is much less toxic and accumulates in the brain and would hence be able to treat the neurological sequelae of NPC. We hope our studies will pave the way to explore this new concept for treatment of this incurable disease.