SBIR-STTR Award

Alzheimer's Disease is a neurodegenerative disease characterized by a progressive decline in cognitive function and a corresponding accumulation of ?-amyloid plaques and neurofibrillary tangles, the two hallmark pathologies. Drugs currently available to AD patients manage the disease symptoms by improving neuronal activity, but efficacy diminishes as the disease advances. In tauopathies such as AD, the accumulation of tau correlates closely with neuronal loss and decline of cognitive function. The novel targeted approach to AD drug development proposed by Aquinnah Pharmaceuticals stems from discoveries made by Dr. Ben Wolozin (Boston University and co-founder of Aquinnah) and his lab, in which tau pathology (in both AD brain samples and animal models) was observed to be present in stress granules (SG). Aquinnah is advancing these compelling findings to identify molecules that inhibit the formation of tau-SGs as a novel treatment for AD.!The overall objective of this SBIR Phase 1 application is to develop several different biologically-relevant tau-SG assays to select the most promising and biologically relevant hits from our currently ongoing HTS, which will then be evaluated further for exploratory ADME and brain penetration analysis. The successful completion of this Phase 1 SBIR will result in the identification of compounds that modulate tau-SGs and are candidates for a Phase 2 medicinal chemistry hit-to-lead and lead optimization program to further develop as novel drugs for the treatment of AD.

Public Health Relevance Statement:
Project Narrative Alzheimer's Disease is a significant burden to society for which there are currently no effective treatments, which means there is a dire need for novel therapeutic approaches in this field. This proposal aims to optimize new therapeutic compounds that prevent and reverse stress granule aggregates, and to develop a lead drug candidate that can be tested in animal models and brought to the clinic. !

Project Terms:
abeta accumulation; advanced disease; Affect; Alzheimer's Disease; Amyloid; Animal Model; base; Biological; Biological Assay; Biology; Boston; Brain; Brain Diseases; Cells; Cellular Assay; Chemicals; Clinic; cognitive function; Complement; Cytoplasmic Granules; Dementia; Dependovirus; Development; Disease Management; Dose; drug candidate; Drug Compounding; drug development; Drug Kinetics; drug metabolism; Drug Screening; Drug Targeting; effective therapy; Elderly; Ensure; Failure; Human; Impaired cognition; improved; In Vitro; induced pluripotent stem cell; inhibitor/antagonist; Lead; lead optimization; Membrane; Modeling; Molecular; Mus; Nerve Degeneration; Neuroblastoma; Neurodegenerative Disorders; Neurofibrillary Tangles; neuron loss; Neurons; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; Pathologic; Pathology; Pathway interactions; Patients; Penetration; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; prevent; programs; Proteins; response; RNA Binding; RNA-Binding Proteins; Role; Safety; Sampling; screening; Senile Plaques; Series; Small Business Innovation Research Grant; small molecule; small molecule inhibitor; Societies; stem; Stress; symptomatic improvement; tau aggregation; tau expression; tau Proteins; Tauopathies; Testing; Translations; Universities; Validation

Alzheimer’s Disease is a neurodegenerative disease characterized by a progressive decline in cognitive function and a corresponding accumulation of ?-amyloid plaques and neurofibrillary tangles, the two hallmark pathologies. Drugs currently available to AD patients manage the disease symptoms by improving neuronal activity, but efficacy diminishes as the disease advances. In tauopathies such as AD, the accumulation of tau correlates closely with neuronal loss and decline of cognitive function. The novel targeted approach to AD drug development proposed by Aquinnah Pharmaceuticals stems from discoveries made by Dr. Ben Wolozin (Boston University and co-founder of Aquinnah) and his laboratory, in which tau pathology (in both AD brain samples and animal models) was observed in stress granules (SG). Aquinnah is advancing these compelling findings to further the development of novel molecules that inhibit the formation of tau-SGs as a novel treatment for AD that were identified in SBIR Phase I. The overall objective of this SBIR Phase II application is to perform a medicinal chemistry hit-to-lead and lead optimization program to advance our novel compounds for the treatment of AD.

Public Health Relevance Statement:
Project Narrative Alzheimer's Disease is a significant burden to society for which there are currently no effective treatments; therefore, there is a dire need for novel therapeutic approaches in this field. This proposal aims to develop a lead drug candidate that will be disease-modifying, and can be tested in animal models and brought to the clinic. !

Project Terms:
abeta accumulation; advanced disease; Alzheimer's Disease; Alzheimer's disease brain; Alzheimer's disease model; Alzheimer's disease patient; Alzheimer's disease therapeutic; Alzheimer's disease therapy; analog; Animal Model; Behavioral; Biological; Biological Assay; Biology; Boston; Canis familiaris; Cells; cerebral atrophy; Chemicals; cholinergic neuron; Chronic stress; Clinic; cognitive function; Complex; Deposition; design; Development; Disease; Disease Management; Disease Progression; drug candidate; drug development; effective therapy; efficacy testing; Environment; Functional disorder; Genetic Polymorphism; Grant; high throughput screening; Human; Impaired cognition; improved; in vivo; Industry Standard; inhibitor/antagonist; knock-down; Laboratories; Laboratory Research; Lead; lead optimization; Link; Liquid substance; medication safety; Membrane; Memory Loss; Messenger RNA; Molecular Target; mouse model; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; neuron loss; Neurons; new therapeutic target; novel; novel therapeutic intervention; Oral; Pathologic; Pathology; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; pharmacophore; Phase; phase 1 study; Process; programs; Proteins; proteostasis; Rattus; response; Role; safety assessment; safety study; Sampling; screening; Senile dementia; Senile Plaques; Series; Small Business Innovation Research Grant; small molecule; small molecule inhibitor; Societies; Source; stem; Stress; stress granule; stress reduction; Structure; symptomatic improvement; Synapses; targeted treatment; tau aggregation; tau interaction; tau Proteins; Tauopathies; Testing; therapeutic development; Toxicology; Transgenes; Translating; Universities