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

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2021 · $41,240

## Abstract

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:** 10265844
- **Project number:** 3R01NS114413-02S1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Leslie N Aldrich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $41,240
- **Award type:** 3
- **Project period:** 2020-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10265844

## Citation

> US National Institutes of Health, RePORTER application 10265844, Development of autophagy modulators for evaluation as a therapeutic strategy for Niemann-Pick Type C (3R01NS114413-02S1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10265844. Licensed CC0.

---

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