# Therapeutic Targets for Niemann-Pick Type C Neurodegeneration

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $563,089

## Abstract

ABSTRACT
Niemann-Pick disease type C (NPC) is 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 this application: to define critical targets in CNS disease
pathogenesis that can be exploited by drug development efforts. Our central hypothesis is that NPC1 deficiency
causes toxicity in both neurons and oligodendrocytes that underlies NPC neuropathology. Moreover, we
hypothesize that this toxicity can be rescued by novel therapeutic strategies aimed at reducing the intracellular
lipid storage that is characteristic of the disease or by correcting the misfolding of mutant NPC1 protein. These
notions are based upon robust preliminary data supporting our model of NPC pathogenesis and the use of
innovative therapeutic approaches to rescue disease phenotypes. 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). These studies are expected to establish that targeting intracellular lipid storage using optimized sHDLs
and modulating mutant NPC1 proteostasis will ameliorate disease phenotypes. Moreover, we expect to
demonstrate an important, yet under-studied role for oligodendrocyte lineage cells in NPC neuropathology.

## Key facts

- **NIH application ID:** 10468243
- **Project number:** 5R01NS122746-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** ANDREW P LIEBERMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $563,089
- **Award type:** 5
- **Project period:** 2021-08-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468243

## Citation

> US National Institutes of Health, RePORTER application 10468243, Therapeutic Targets for Niemann-Pick Type C Neurodegeneration (5R01NS122746-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10468243. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*