Increased vulnerability to ferroptosis in Niemann-Pick disease type C

About This Grant

Niemann-Pick Disease Type C (NPC) is a fatal pediatric neurodegenerative disorder caused by mutations in NPC1 or NPC2, affecting fewer than 200,000 individuals globally. There is no cure or disease-modifying therapy approved for NPC in the United States, and further research to elucidate pathogenic mechanisms remains a high priority for effective therapeutic development. Despite well-characterized cellular pathologies, including endo-lysosomal enlargement, mitochondrial damage, iron and calcium dysregulation, lipid peroxidation, and chronic inflammation, how these diverse pathologies converge to drive disease progression remains unclear. This gap hampers the development of disease-modifying therapies. We hypothesize that NPC neurodegeneration arises from chronic cellular stress that culminates in ferroptosis, an iron-dependent cell death pathway driven by lethal lipid peroxide accumulation, and further characterized by lysosomal dysfunction, mitochondrial damage, iron and calcium dysregulation, and chronic inflammation. As a corollary, anti-ferroptotic drugs will delay or prevent the progression of this harmful process and, by extension, slow down cell death by this mechanism. Our preliminary data supports this hypothesis by showing: 1) elevated lipid peroxidation in NPC patient cells compared to sex- and aged-matched controls; 2) increased vulnerability of NPC cells to ferroptotic death, reversible by anti-ferroptotic compounds J147 and CMS121, which were developed by co-PI Dr. Maher, and 3) evidence of differential anterior-to-posterior ferroptotic activation in cerebellar Purkinje cells that mirrors the spatiotemporal pattern of neurodegeneration in NPC. We propose to test this hypothesis by pursuing the following Specific Aim: Characterize ferroptosis along the anterior-to-posterior axis of neurodegeneration in the NPC cerebellum and evaluate the ability of J147 and CMS121 to reduce NPC pathology and delay clinical symptoms in a mouse model of NPC. Significance: Successful completion of our study will help determine the extent of the contribution of ferroptosis to NPC pathogenesis and could establish ferroptosis as a therapeutic target, enabling repurposing of anti-ferroptotic drugs to slow neurodegeneration. Furthermore, both J147 and CMS121 already have Investigational New Drug approval so they could be rapidly moved to the clinic if proven effective in these studies