# Validation of Modulators of PGRN as Novel Therapeutics for Frontotemporal Dementi

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $800,931

## Abstract

Haploinsufficiency of the GRN gene encoding Progranulin (PGRN) is the genetic cause for a common form of
frontotemporal lobar degeneration (FTLD) giving rise to a distinctive frontotemporal dementia syndrome. It is
the second most common form of dementia after Alzheimer's disease and currently no effective cure exists for
either form of neurodegeneration. Complete lack of PGRN causes a form of neuronal ceroid lipofuscinosis
(NCL), a genetically heterogeneous form of lysosomal storage disease in which the digestion of cellular
membranes and glycosphingolipids is impaired, resulting in the accumulation of large misshaped lysosomes
especially in neurons. This discovery has shaped our current understanding of GRN haploinsufficiency as a
genetically distinct latent form of lysosomal dysfunction that accelerates the `normal' progressively diminishing
lysosomal capacity during aging. Lysosomal dysfunction syndromes are thought to induce the production of
inflammatory cytokines in part through the reduced generation of physiological lipid ligands for inflammation
suppressing nuclear hormone receptors, which further promotes neurodegeneration by increasing microglial
activation and synaptophagy. FTLD caused by GRN haploinsufficiency offers a unique therapeutic avenue
by increasing gene expression from the remaining functional allele. In theory, doubling of baseline GRN
expression should completely negate the risk for this form of FTLD in affected individuals. Our team has
developed a comprehensive small molecule discovery strategy that has led to the identification of several
chemically and mechanistically distinct classes of GRN transcriptional enhancers. The purpose of this project
is to investigate the biochemical and cell biological mechanisms through which these small molecules act on
the GRN gene and optimize their specificity and preclinical efficacy. This will be achieved by pursuing three
major aims: Aim 1 Prioritize and optimize PGRN enhancers for preclinical development based upon efficacy
and functional signatures from integrated ex vivo and in vivo studies; Aim 2 Determine the translational
potential of PGRN enhancing compounds by evaluating their ability to normalize the cellular and brain
transcriptome and lipidome; and Aim 3 Determine the translational potential of PGRN enhancing compounds
by investigating their effects on cellular membrane lipid composition and the lysosomal lipidome and proteome.

## Key facts

- **NIH application ID:** 9988543
- **Project number:** 5R01NS108115-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** STEPHEN J HAGGARTY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $800,931
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988543

## Citation

> US National Institutes of Health, RePORTER application 9988543, Validation of Modulators of PGRN as Novel Therapeutics for Frontotemporal Dementi (5R01NS108115-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9988543. Licensed CC0.

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