NPC1 protein misfolding in niemann-pick type C disease

The National Institute of Neurological Disorders and Stroke awarded $640,674 to the Regents of the University of Michigan on August 21, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to support research on NPC1 protein misfolding in Niemann-Pick Type C disease.

The funded research targets mutant NPC1 protein misfolding to recover function and exert therapeutic benefit in Niemann-Pick C models. The project will develop novel derivatives of the modified hydroxycholesterol called MO56HC and assess their ability to promote the folding, trafficking, and functional recovery of NPC1 containing missense mutations that cause the disease. The investigator team will employ biochemical, genetic, chemical, behavioral, and histological approaches using human induced neurons and mouse models to establish activity of NPC1 chemical chaperones and advance toward disease-modifying therapies for this invariably fatal autosomal recessive lysosomal disorder that causes progressive neurodegeneration and early death in affected patients.

Work is performed in Ann Arbor, Michigan, with a period of performance extending through July 31, 2031. This is a Project Grant, the assistance type standard for investigator-initiated research at NINDS. The University of Michigan's Office of Research and Sponsored Projects administered the award.

Abstract

Niemann-pick disease type C is an invariably fatal autosomal recessive lysosomal disorder affecting all ages. Patients develop a clinically heterogeneous phenotype that includes severe, progressive neurodegeneration and early death. This disease is commonly caused by loss-of-function mutations in the NPC1 gene, encoding a multipass transmembrane glycoprotein required for exporting unesterified cholesterol from late endosomes and lysosomes. Most often, disease-causing missense mutations trigger misfolding of the NPC1 protein in the endoplasmic reticulum, leading to its degradation. Despite our understanding of the effects manifested by these mutations, there are currently few FDA-approved therapies and patients most often DIE in childhood, reflecting a significant unmet medical need. Our long-term goal is to contribute toward the development of disease-modifying therapies for individuals with niemann-pick C. The next step toward attaining this goal is to pursue the overall objective of this application: to target mutant NPC1 protein misfolding to recover function and exert therapeutic benefit in niemann-pick C models. Our central hypothesis is that novel derivatives of the modified hydroxycholesterol called MO56HC promote the folding, trafficking, and functional recovery of NPC1 containing missense mutations and rescue disease phenotypes. This hypothesis springs from a strong scientific premise based on published literature supporting the development of proteostatic therapies for niemann-pick C. Additionally, our rigorous preliminary data indicate the generation of a potent, biologically active lead compound and both human induced neurons (INEURONS) and mouse models for assessing this novel therapeutic approach. We will use biochemical, genetic, chemical, behavioral, and histological approaches to: establish activity of NPC1 chemical chaperones in human INEURONS expressing disease-causing missense mutations (aim 1); optimize novel chemical chaperones for NPC1 (aim 2); and determine the extent to which an NPC1 chemical chaperone rescues phenotypes in mice expressing human I1061T NPC1 (aim 3). We expect that these studies will provide proof of concept justification to further develop this strategy as a therapy for niemann-pick C patients.