This project seeks to develop a novel disease-modifying compound for AD (AD) by targeting the underlying mechanism of synapse loss. Synapse loss is tightly correlated with cognitive decline and is triggered initially by amyloid-ß peptide oligomer accumulation. Soluble amyloid-ß oligomers bind to Prion Protein, thereby engaging mGluR5 as a co-receptor, and activating PTK2B (Pyk2) and Fyn kinases to couple with Tau pathology and synapse loss. Genetic knockout studies in rodents have shown that knockout of mGluR5 prevents disease onset, and our target sits directly upstream of PTK2B, a GWAS hit in AD. These features provide strong evidence of mGluR5 as a promising therapeutic target for developing novel Alzheimer's treatments. Allyx Therapeutics has obtained an exclusive license for use of BMS-984923 in neurodegenerative diseases from Bristol Meyers Squibb and Yale University. Preliminary studies demonstrate robust efficacy of this small molecule treatment in multiple preclinical mouse AD models. Drug treatment recovers synapse density, restores hippocampal activity, and returns memory performance to normal levels. Pre-clinical development has characterized a highly drug-like profile allowing for the recent approval of the BMS-984923 commercial IND for the initiation of first time in human clinical studies. The overall goal is to develop disease-modifying oral drug effective to slow, halt or partially reverse AD progression both in the MCI state and in mild dementia.
Public Health Relevance Statement: PUBLIC HEALTH NARRATIVE Today, no conclusive disease-modifying therapies for AD are available. Synapse loss in AD brain has been tightly correlated with symptoms and is triggered initially by amyloid beta peptide accumulation. We have mapped a pathway from amyloid-ß oligomers to synapse loss. Central to this pathway is the transmembrane receptor mGluR5, a metabotropic glutamate receptor, which when complexed with cellular prion protein triggers synaptic dysfunction and recruits immune mediators for microglial mediated pruning. We have developed an orally bioavailable small molecule drug which selectively blocks AD dependent damage while preserving normal physiologic signaling through mGluR5. Here, we aim to develop this compound to slow, halt or partially reverse AD progression both in the MCI state and in mild dementia.
Project Terms: Elderly; advanced age; elders; geriatric; late life; later life; older adult; older person; senior citizen; 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; Biological Response Modifiers; Biomodulators; Immune Mediators; Immune Mediators/Modulators; Immune Regulators; immunomodulatory biologics; Biotechnology; Biotech; Brain; Brain Nervous System; Encephalon; capsule; Capsules; Cause of Death; Censuses; Clinical Research; Clinical Study; Cognition; Cytoplasmic Granules; granule; Deglutition; Swallowing; Disease; Disorder; Dosage Forms; Pharmacotherapy; Drug Therapy; drug treatment; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Food; Food or Food Product; Gelatin; Goals; Hippocampus (Brain); Ammon Horn; Cornu Ammonis; Hippocampus; hippocampal; Human; Modern Man; Learning; Maps; Memory; Mus; Mice; Mice Mammals; Murine; Pathology; Patients; Pharmacokinetics; Drug Kinetics; Kinases; Phosphotransferase Gene; Transphosphorylases; Phosphotransferases; Sham Treatment; sham therapy; Placebos; Public Health; Quality Control; QOL; Quality of life; Rodentia; Rodents Mammals; Rodent; Safety; Sales; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Signal Transduction; gastric; Stomach; Suspension substance; Suspensions; Synaptic; synapse; Synapses; Time; Universities; Amyloid beta-Protein; Alzheimer beta-Protein; Alzheimer's Amyloid beta-Protein; Alzheimer's amyloid; Amyloid Alzheimer's Dementia Amyloid Protein; Amyloid Beta-Peptide; Amyloid Protein A4; Amyloid ß; Amyloid ß-Peptide; Amyloid ß-Protein; Aß; a beta peptide; abeta; amyloid beta; amyloid-b protein; beta amyloid fibril; soluble amyloid precursor protein; Measures; tau Proteins; MT-bound tau; microtubule bound tau; microtubule-bound tau; tau; tau factor; Ï Proteins; Caregivers; Care Givers; Mediating; Uncertainty; doubt; base; density; improved; Clinical; Phase; Physiological; Physiologic; Metabotropic Glutamate Receptors; Ensure; Individual; Licensing; Disease Progression; Dysfunction; Physiopathology; pathophysiology; Functional disorder; disease onset; disorder onset; Onset of illness; Phase 2 Clinical Trials; phase II protocol; Phase II Clinical Trials; Therapeutic; Genetic; Cognitive Disturbance; Cognitive Impairment; Cognitive decline; Cognitive function abnormal; Disturbance in cognition; cognitive dysfunction; cognitive loss; Impaired cognition; Knowledge; protein B; Kilogram; Complex; Oral; Route; Amentia; Dementia; 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; GRIK1 gene product; metabotropic glutamate receptor 5; Performance; Receptor Protein; receptor; Animal Models and Related Studies; model of animal; model organism; Animal Model; Toxicities; Toxic effect; novel; technological innovation; Property; Molecular Interaction; Binding; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; Pharmacologic Substance; preventing; prevent; small molecule; Acidity; CAKB; CAKbeta; FAK2; PTK2B; PYK2; cell adhesion kinase beta; proline-rich tyrosine kinase 2; PTK2B gene; Dose; Symptoms; Data; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Knock-out; Knockout; Development; developmental; nano; Pathway interactions; pathway; pre-clinical; preclinical; genome wide association study; GWA study; GWAS; genome wide association; genome wide association scan; genome wide association studies; genomewide association scan; genomewide association studies; genomewide association study; whole genome association analysis; whole genome association studies; whole genome association study; Outcome; manufacturing process; innovation; innovate; innovative; abeta oligomer; Amyloid ß oligomer; amyloid beta oligomer; aß oligomer; Alzheimer's disease model; AD model; alzheimer model; therapeutic target; commercial application; commercialization; FDA approved; PrP; PrP Proteins; Prion Proteins; mild cognitive impairment; mild cognitive disorder; phase II trial; phase 2 trial; Industry Standard; Formulation; dementia care; clinical development; preclinical development; pre-clinical development; recruit; preservation; Aducanumab; BIIB037; aduhelm
