# Evaluation of Alzheimers disease experimental small molecule therapeutics in the models of Amyotrophic lateral sclerosis

> **NIH NIH R43** · EPIGEN BIOSCIENCES, INC. · 2021 · $449,984

## Abstract

Abstract
The endoplasmic reticulum (ER) protein sigma-1 receptor represents a unique chaperone activity in the central
nervous system, and it exerts a potent influence on several neurotransmitter systems. S1R is distinct from
GPCRs and ionotropic receptors and is expressed in neurons in multiple brain regions in post-mortem human
brains. S1R plays a modulatory role in biological mechanisms associated with neurodegeneration. S1R ligands
activation is known to improve cognition, promote cell survival, and facilitate the release of the neuroprotectant
BDNF.
The broad objective is to evaluate selective sigma1 receptor (S1R) ligands toward commercial development for
the treatment of Amyotrophic Lateral Sclerosis (ALS). During feasibility studies under grant R41AG043243, we
identified EPGN644, a selective S1R small molecule ligand with CNS exposure with demonstrated efficacy in
mouse models of AD (Tg4510) upon oral dosing. Lead optimization efforts identified EPGN2544 and EPGN2665
as alternatives to EPGN644 with a superior overall profile and with the novel composition of matter claims.
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by progressive
muscle atrophy and paralysis due to the death of upper and lower Motor Neurons. The broad objective is to
evaluate selective sigma1 receptor ligands toward commercial development for the treatment of ALS. A recent
report indicated that PRE-084, a Sigma1R literature tool compound, demonstrated neuroprotection, neurite
elongation, and efficacy in a SOD1G93A mouse model of ALS. Taking together this literature precedence for the
benefit of S1R ligands in an ALS mouse model, and having a well-optimized S1R ligand (EPGN2665) in hand,
we propose to conduct efficacy studies in human induced pluripotent stem cells (iPSC) derived motor neurons,
and in two widely used mouse models of ALS (TDP-43 and SOD1G93A).

## Key facts

- **NIH application ID:** 10259064
- **Project number:** 1R43AG071335-01A1
- **Recipient organization:** EPIGEN BIOSCIENCES, INC.
- **Principal Investigator:** Satheesh B Ravula
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $449,984
- **Award type:** 1
- **Project period:** 2021-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10259064

## Citation

> US National Institutes of Health, RePORTER application 10259064, Evaluation of Alzheimers disease experimental small molecule therapeutics in the models of Amyotrophic lateral sclerosis (1R43AG071335-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10259064. Licensed CC0.

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