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NIH grant 1R01NS150245-01: NPC1 protein misfolding in Niemann-Pick type C disease
Institute: {'code': 'NS', 'abbreviation': 'NINDS', 'name': 'National Institute of Neurological Disorders and Stroke', 'admin_org_id': '12500053', 'admin_funding_url': ''}. PI: Brian S J Blagg. Award: $640674.
Start: 2026-08-21T00:00:00.
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.document fetched 2026-08-30 02:46