# Development of autophagy modulators for evaluation as a therapeutic strategy for Niemann-Pick Type C

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $385,586

## Abstract

Autophagy is a cellular homeostasis pathway that has been implicated in numerous diseases. One of these
diseases, Niemann-Pick disease type C (NPC), is an autosomal recessive, neurodegenerative disorder.
Mutations in the NPC1 gene occur in 95% of patients, and the resultant NPC1 protein is misfolded and degraded
or no longer capable of facilitating intracellular trafficking of lipids and cholesterol through the lysosome. There
is currently no FDA-approved therapy for NPC, and thus there is a critical need to develop effective therapeutics
to meet the needs of NPC patients. The long-term goal of this research is to address this need through the
development of small-molecule autophagy modulators that restore lipid homeostasis in vivo. The overall
objective of this proposal is to identify and optimize small molecules that modulate autophagy, improve the NPC
phenotype in vitro, and restore lipid homeostasis in vivo while also extending life span. The rationale for this
research is that various mechanisms of autophagy modulation, including early-stage inhibition, late-stage
inhibition, and activation, have been reported to have potential therapeutic benefit in models of NPC. The central
hypothesis of this research is that small molecules that modulate autophagy will alleviate cholesterol
accumulation and extend life span of NPC mice. However, it is still unclear what mechanism of autophagy
modulation is most beneficial, and this question will be a central focus of this research through unbiased
identification of autophagy modulators that improve the NPC phenotype. This approach is innovative because it
departs from the status quo of developing autophagy modulators and then exploring their effects in NPC and
instead uses phenotypic screens to identify modulators that have a positive impact on NPC phenotypes with
subsequent determination of the mechanism of autophagy modulation. Mass spectrometry imaging will be used
as a novel method to determine modulator mechanism and to evaluate efficacy of autophagy modulators in vivo
through the analysis of protein and lipid changes, which will also aid in the identification of biomarkers. The
proposed research is significant because it will identify which mechanism of autophagy modulation is most
beneficial in NPC, it will provide novel, small-molecule autophagy modulators with efficacy in NPC, and it will
provide new strategies for the assessment of small-molecule mechanism in vivo without labeled probes. These
advances will greatly contribute to the long-term goal of bringing new therapeutic options to NPC patients.

## Key facts

- **NIH application ID:** 9860775
- **Project number:** 1R01NS114413-01
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Leslie N Aldrich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,586
- **Award type:** 1
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9860775

## Citation

> US National Institutes of Health, RePORTER application 9860775, Development of autophagy modulators for evaluation as a therapeutic strategy for Niemann-Pick Type C (1R01NS114413-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9860775. Licensed CC0.

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