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

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R43AG071335-01A1
Agency Tracking Number: R43AG071335
Amount: $449,984.00
Phase: Phase I
Program: SBIR
Solicitation Topic Code: NIA
Solicitation Number: PA20-260
Timeline
Solicitation Year: 2020
Award Year: 2021
Award Start Date (Proposal Award Date): 2021-06-01
Award End Date (Contract End Date): 2022-05-31
Small Business Information
10225 BARNES CANYON RD, STE A104
San Diego, CA 92121-2734
United States
DUNS: 963248807
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 SATHEESH RAVULA
 (619) 200-5689
 sravula@epigenbiosciences.com
Business Contact
 SATHEESH RAVULA
Phone: (858) 657-0918
Email: sravula@epigenbiosciences.com
Research Institution
N/A
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).Narrative
Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disorder characterized by progressive
muscle atrophy and paralysis due to death of upper and lower Motor Neurons (MNs). The broad objective is to
evaluate selective sigma1 receptor (S1R) ligands toward commercial development for the treatment of ALS.

* Information listed above is at the time of submission. *

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