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

Award Number: R43AG071335
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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).


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	EPIGEN BIOSCIENCES INC	6725 MESA RIDGE RD	SAN DIEGO	CA	92121	SAN DIEGO	USA	Aging Research	000	1	5/25/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $449,984 )
2021	2021	EPIGEN BIOSCIENCES INC.	10225 BARNES CANYON RD, STE A104	SAN DIEGO	CA	92121	SAN DIEGO	USA	Aging Research	000	1	5/19/2021	NEW	$449,984
														Subtotal = $449,984

Grand Total All Awards = $449,984

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

Award Number: R43AG071335

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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