Therapeutic targets for Niemann-Pick type C neurodegeneration

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STATEMENT OF WORK This application seeks supplemental support for R01 NS122746, entitled “Therapeutic targets for Niemann-Pick type C neurodegeneration” to promote diversity in health-related research. The goal of this supplement is to support the training of Adele Correia, a PhD trainee enrolled in the Program in Biomedical Sciences at the University of Michigan. Ms. Correia’s thesis project focuses on Niemann-Pick disease type C (NPC), an invariably fatal autosomal recessive lipid storage disorder affecting all ages. Patients develop a clinically heterogeneous phenotype that includes severe, progressive neurodegeneration, hepatomegaly, and early death. NPC is commonly caused by loss-of-function mutations in the NPC1 gene (95% of cases), encoding a multipass transmembrane glycoprotein required for exporting unesterified cholesterol from late endosomes and lysosomes. Despite our emerging understanding of the role of NPC1 in intracellular cholesterol trafficking, a diagnosis of NPC remains particularly bleak. There are currently no FDA-approved disease modifying therapies and patients most often die in childhood, reflecting both gaps in our current knowledge of disease pathogenesis and a significant unmet medical need. Our long-term goal is to contribute toward the development of disease-modifying therapies for NPC patients. The next step in attaining this goal is to pursue the overall objective of the parent R01 grant: to define critical targets in CNS disease pathogenesis that can be exploited by drug development efforts. We will use genetic, biochemical, histological, and phenotypic analyses to: establish the extent to which neuronal lipid storage and toxicity are rescued by optimized synthetic HDL nanoparticles (Aim 1); determine the role of oligodendrocyte lineage cells in NPC neuropathology (Aim 2); and establish effects of proteostasis regulators in humanized NPC1 model systems (Aim 3). The work proposed in this supplement is an extension of Aim 1 of the parent R01 grant. Here, we propose to study the therapeutic benefits of synthetic HDL nanoparticles in human induced neurons expressing a common disease-causing variant of NPC1 (I1061T NPC1). Beneficial effects on cell survival, lipid storage, and gene expression will be quantified. The most promising formulation will be tested in a new mouse model of NPC which expresses human I1061T NPC1. Effects on disease phenotypes including behavioral abnormalities, survival, neuronal lipid storage, and gene expression changes will be quantified. These studies are expected to establish that targeting intracellular lipid storage using optimized synthetic HDLs will ameliorate disease phenotypes.