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).
Public Health Relevance Statement: 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.
Project Terms: Adult ; 21+ years old ; Adult Human ; adulthood ; Age ; ages ; Alanine ; Alzheimer's Disease ; AD dementia ; Alzheimer ; Alzheimer Type Dementia ; Alzheimer disease ; Alzheimer sclerosis ; Alzheimer syndrome ; Alzheimer's ; Alzheimer's disease dementia ; Alzheimers Dementia ; Alzheimers disease ; Primary Senile Degenerative Dementia ; dementia of the Alzheimer type ; primary degenerative dementia ; senile dementia of the Alzheimer type ; Amyotrophic Lateral Sclerosis ; Amyotrophic Lateral Sclerosis Motor Neuron Disease ; Gehrig's Disease ; Lou Gehrig Disease ; Autopsy ; necropsy ; postmortem ; Axon ; Biological Availability ; Bioavailability ; Biologic Availability ; Physiologic Availability ; Body Weight ; Brain ; Brain Nervous System ; Encephalon ; Cell Survival ; Cell Viability ; High Pressure Liquid Chromatography ; HPLC ; High Performance Liquid Chromatography ; High Speed Liquid Chromatography ; Chromosome 9 ; Codon Nucleotides ; Codon ; Cognition ; Cessation of life ; Death ; Dendrites ; DNA-Binding Proteins ; Pharmacotherapy ; Drug Therapy ; drug treatment ; Electromyography ; Endoplasmic Reticulum ; Ergastoplasm ; Feasibility Studies ; Female ; Genes ; Glycine ; Aminoacetic Acid ; Grant ; Hand ; Histology ; Human ; Modern Man ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Ligands ; Literature ; male ; Transgenic Mice ; Motor Neurons ; Motor Cell ; motoneuron ; Mus ; Mice ; Mice Mammals ; Murine ; Muscular Atrophy ; Muscle Atrophy ; muscle breakdown ; muscle degradation ; muscle deterioration ; muscle loss ; muscle wasting ; Nerve Degeneration ; Neuron Degeneration ; neural degeneration ; neurodegeneration ; neurodegenerative ; neurological degeneration ; neuronal degeneration ; Neurons ; Nerve Cells ; Nerve Unit ; Neural Cell ; Neurocyte ; neuronal ; Neurotransmitters ; Nerve Transmitter Substances ; Phenotype ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Play ; Proteins ; Research Design ; Study Type ; study design ; Role ; social role ; sciatic nerve ; Spinal Cord ; Medulla Spinalis ; Time ; Toxicology ; Work ; Neurites ; Brain-Derived Neurotrophic Factor ; BDNF ; TimeLine ; improved ; sample collection ; specimen collection ; Clinical ; Phase ; Biological ; Evaluation ; Progress Reports ; Neuroprotective Agents ; Neuroprotectants ; Neuroprotective Drugs ; Molecular Chaperones ; Chaperone ; Agonist ; Letters ; TAR DNA-binding protein 43 ; TDP-43 ; TDP43 ; protein TDP43 ; protein TDP-43 ; tool ; Whole Blood ; programs ; Hour ; Oral ; System ; Spinal ; Palsy ; Plegia ; paralysis ; paralytic ; Paralysed ; Degenerative Neurologic Diseases ; Degenerative Neurologic Disorders ; Nervous System Degenerative Diseases ; Neural Degenerative Diseases ; Neural degenerative Disorders ; Neurodegenerative Diseases ; Neurologic Degenerative Conditions ; degenerative diseases of motor and sensory neurons ; degenerative neurological diseases ; neurodegenerative illness ; Neurodegenerative Disorders ; sigma-1 receptor ; mutant ; Receptor Protein ; receptor ; synapse formation ; synaptogenesis ; neuroprotection ; Transact ; SOD-1 ; SOD-1 protein ; SOD1 ; SOD1 gene ; SOD1 gene product ; superoxide dismutase 1 ; novel ; G Protein-Complex Receptor ; G Protein-Coupled Receptor Genes ; GPCR ; G-Protein-Coupled Receptors ; disorder model ; Disease model ; Reporting ; Drug Exposure ; Maximal Tolerated Dose ; Maximally Tolerated Dose ; Maximum Tolerated Dose ; Modeling ; response ; CNS Nervous System ; Central Nervous System ; Neuraxis ; Rotarod Assay ; Rotarod Method ; Rotarod Test ; Rotarod Performance Test ; Brain region ; Tissue Sample ; small molecule ; Dose ; DNA Alteration ; DNA mutation ; Genetic mutation ; Sequence Alteration ; genomic alteration ; DNA Sequence Alteration ; Data ; Strategic Planning ; The Jackson Laboratory ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Monitor ; Preparation ; Process ; sex ; Development ; developmental ; familial amyotrophic lateral sclerosis ; fALS ; familial ALS ; efficacy evaluation ; efficacy analysis ; efficacy assessment ; efficacy examination ; evaluate efficacy ; examine efficacy ; scale up ; mouse model ; murine model ; Alzheimer's disease model ; AD model ; alzheimer model ; induced pluripotent stem cell ; iPS ; iPSC ; iPSCs ; therapy development ; develop therapy ; intervention development ; treatment development ; small molecule therapeutics ; experimental study ; experiment ; experimental research ; efficacy study ; lead optimization ; experimental group ; amyotrophic lateral sclerosis therapy ; ALS therapy ; ALS treatment ; amyotrophic lateral sclerosis treatment ; fused in sarcoma ; efficacy outcomes ;
