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

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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).