Modulators of Rab9 Expression for the Treatment of Niemann-Pick C Disease

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DESCRIPTION (provided by applicant): NPC1 disease is a severe lysosomal lipidosis in which the egress of cholesterol and other lipids from the endosomal/lysosomal (E/L) system is impeded, leading to severe neurodegeneration and premature demise. At present there are no treatment options for patients with NPC1 or other lysosomal storage disorders (LSDs) that present with neurodegenerative phenotypes, mainly due to the inability of corrective proteins to cross the blood-brain barrier. Therefore, a new paradigm is needed to address the large family of LSDs with neuropathology. We hy7pothesiae that suppressor proteins can be identified for the LSDs and that the expression of these proteins can be modulated via small chemical molecules that can gain access to the central nervous system and limit the severity of these disorders. In essence, this approach bypasses the defective lysosomal protein and therefore we have termed it "Orphan receptor bypass therapy" or "ORByT". We will first carry out a high-throughput screen to identify pharmacologically active, for ORByT-relevant small molecules for NPC1 disease. Using Rab9 as a "suppressor" candidate for NPC1, we will use the recently established high throughput screening pharmacologically active for NPC1 disease. Second, we will evaluate candidate molecules for the therapeutic potential. Small molecule compounds identified in Aim 1 will be tested for their ability to correct the NPC1 lipid transport block phenotype. Those compounds that are confirmed to restore lipid transport in NPC cells will be evaluated in vivo using an NPC mouse model to determine their therapeutic potential prior to further development to improve their potency, toxicity profile, and brain delivery. Successful identification of small molecules will provide "Proof-of-principle" for the ORByt strategy and a new approach to therapy for NPC1 and other devastating neurological LSDs. PUBLIC HEALTH RELEVANCE: Diseases that affect the brain are currently difficult if not impossible to treat. We are developing a novel approach to treat devastating genetic diseases with neurologic involvement that are currently untreatable.