# Targeting the lysosome-mitochondria axis in neurodegenerative lysosomal storage diseases - Lessons from telomerase immortalization

> **NIH NIH R21** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $295,531

## Abstract

We have identified a link between telomerase immortalization and correction of the NPC1
lipid storage phenotype. Furthermore, we have recently identified the stress transcription
factor NRF1 as one of the genes induced by telomerase, especially in cells that are already
under stress such as Niemann-Pick C disease cells characterized by lysosomal
cholesterol storage. These results are particularly exciting since among many cellular
functions assigned to NRF1 it was recently shown to be a central player in cellular
cholesterol homeostasis.
We subsequently determined that ectopic expression of NRF1 alone could correct the
NPC1 cholesterol storage phenotype suggesting that NRF1 provides a link between
mitochondria and lysosome function and under stress (disease) conditions NRF1 could
normalize their function. Thus, we have identified a transcription factor that is a novel
target for NPC1 disease and potentially for many other lysosomal storage disorders.
It is known however, that transcription factors are notoriously difficult to drug and
present unique challenges due to their tight and often intricate regulation. For these
reasons we were excited to identify two unique methods for activating NRF1 in target,
disease cells. First, using a novel transcriptional activation assay we have developed we
have identified a group of FDA-approved calcium channel inhibitors that are very potent
activators of NRF1. Second, we have identified an interesting property of telomerase
immortalized NPC1 cells; they secreted exosomes that contain high levels of active NRF1
that are capable of transferring this trasncription factor to target cells.
By targeting NRF1, the goals of this proposal are first to validate its therapeutic
potential to treat NPC1 disease and thus address a great-unmet need. Second, to
evaluate their therapeutic effectiveness in vivo using an animal model of NPC1 disease.
The success of these studies will provide preclinical validation of this novel approach
and provide the rationale for further therapeutic development.

## Key facts

- **NIH application ID:** 10591897
- **Project number:** 1R21HD108675-01A1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** YIANNIS A IOANNOU
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $295,531
- **Award type:** 1
- **Project period:** 2022-09-23 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10591897

## Citation

> US National Institutes of Health, RePORTER application 10591897, Targeting the lysosome-mitochondria axis in neurodegenerative lysosomal storage diseases - Lessons from telomerase immortalization (1R21HD108675-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10591897. Licensed CC0.

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