# Therapeutic targets for Niemann-Pick type C neurodegeneration

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $78,690

## Abstract

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.

## Key facts

- **NIH application ID:** 10620477
- **Project number:** 3R01NS122746-02S1
- **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:** $78,690
- **Award type:** 3
- **Project period:** 2021-08-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10620477

## Citation

> US National Institutes of Health, RePORTER application 10620477, Therapeutic targets for Niemann-Pick type C neurodegeneration (3R01NS122746-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10620477. Licensed CC0.

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