SBIR-STTR Award

Alzheimer's disease (AD) is the leading cause of dementia, with incidence on the rise-clearly central to aglobal health crisis. Clinical symptoms often manifest as a progressive decline in cognitive ability and memoryimpairment but eventually leads to loss of control of vital functions. AD is a slow-developing neurodegenerativedisease for which age is the leading risk factor indicating that aging interventions and lifespan extending drugsmight be AD-effective. Although, hundreds of anti-aging compounds have been identified, very few of thesecompounds have been evaluated on animal models of AD. Our premise is that the AD models of the nematodeC. elegans have much to contribute to the identification of lead candidate drugs that improve neuronal agingand protect against proteostasis disease. We propose to use a novel high-throughput technology to screenmany FDA approved drugs and anti-aging compounds in C. elegans enabling us to test longevity-promotingcompounds that will include a subset with potent effects against AD-related toxicity.AIM 1: Perform a screen on C. elegans AD models with lifespan-extension and FDA-approved drugs. Inthis aim, we plan to screen 300 anti-aging compounds and 200 FDA-approved drugs that target the hallmarksof aging on C. elegans AD models. The screen capitalizes on NemaLife's high throughput screening platformwith phenotypic end-points of mobility declines and survival. Hits will be confirmed by in vivo imaging ofaggregates. This task will generate a compound lead series for AD drug development pipeline.AIM 2. Prioritize lead candidates by addressing critical gaps in preclinical AD drug discovery. Robusttranslation of drugs requires testing lead series with genetically diverse AD strains and also developingcombination therapy to target multiple AD pathways. We will generate recombinant C. elegans strains toaddress genetic diversity in AD and plan to screen the most promising compounds and determine ifinterventions administered at early adult or late adult (onset of symptoms) stages are effective. Finally, a proof-of-principle combination study that involves compounds targeting hallmarks of aging will be piloted against theAD models. This multi-prong approach is expected to de-risk drug failure in mammalian AD models.In summary, we will use a novel NemaLife technology to identify a subset of pharmacological longevityinterventions will exert neuroprotection against AD-relevant stresses. The outcome will establish bothpromising candidates for AD preclinical study and potentially clinical trials and a much-needed work-horse toolin drug discovery that prioritizes compounds for human AD. Project Narrative Alzheimer's disease (AD) is devastating for victims, their families, and society, yet anti-AD treatments remain painfully elusive. Since age is a major risk factor for Alzheimer's disease as well as other age- related chronic diseases, investigating drugs that target hallmarks of aging hold promise for AD therapeutics. Our plan combines a high-throughput microfluidic technology and genetically diverse nematode strains that feature Alzheimer's disease-associated stresses to screen and identify repurposed drugs and anti-aging compounds that are both neuroprotective and extend lifespan, which would be considered priority follow-up interventions for anti-AD impact in higher organisms. Adult ; 21+ years old ; Adult Human ; adulthood ; Age ; ages ; Aging ; 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 ; Animals ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Biology ; Chronic Disease ; Chronic Illness ; chronic disorder ; Clinical Trials ; Combined Modality Therapy ; Multimodal Therapy ; Multimodal Treatment ; combination therapy ; combined modality treatment ; combined treatment ; multi-modal therapy ; multi-modal treatment ; Disease ; Disorder ; Drug Combinations ; Combination Drug Therapy ; Polychemotherapy ; combination chemotherapy ; combination pharmacotherapy ; combined drug therapy ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Family ; Health ; Equus caballus ; Domestic Horse ; Equine ; Equine Species ; Equus przewalskii ; Horses ; Human ; Modern Man ; Incidence ; Insulin ; Humulin R ; Novolin R ; Regular Insulin ; Invertebrates ; Invertebrata ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Libraries ; Longevity ; Length of Life ; life span ; lifespan ; Maintenance ; Nematoda ; Nematodes ; roundworm ; Neurons ; Nerve Cells ; Nerve Unit ; Neural Cell ; Neurocyte ; neuronal ; Organism ; living system ; Pain ; Painful ; Patients ; Peptides ; Pharmacology ; Phenotype ; Risk ; Risk Factors ; Running ; Safety ; Signal Pathway ; Societies ; Somatomedins ; Insulin-Like Growth Factors ; Sulfation Factor ; insulinlike growth factor ; Stress ; Technology ; Testing ; Time ; Tissues ; Body Tissues ; Translations ; Genetic Variation ; Genetic Diversity ; Vertebrates ; Vertebrate Animals ; vertebrata ; Work ; 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 β ; Amyloid β-Peptide ; Amyloid β-Protein ; Aβ ; a beta peptide ; abeta ; amyloid beta ; amyloid-b protein ; beta amyloid fibril ; soluble amyloid precursor protein ; Neurofibrillary Tangles ; neurofibrillary degeneration ; neurofibrillary lesion ; neurofibrillary pathology ; tangle ; tau Proteins ; MT-bound tau ; microtubule bound tau ; microtubule-bound tau ; tau ; tau factor ; τ Proteins ; Population Heterogeneity ; diverse populations ; heterogeneous population ; population diversity ; Caenorhabditis elegans ; C elegans ; C. elegans ; C.elegans ; base ; improved ; Chronic ; Clinical ; Variant ; Variation ; Neurologic ; Neurological ; Ensure ; Failure ; Memory impairment ; Memory Deficit ; memory dysfunction ; Sample Size ; tau-1 ; p-tau ; p-τ ; phospho-tau ; phospho-τ ; phosphorylated tau ; Onset of illness ; disease onset ; disorder onset ; tool ; Life ; fighting ; Complex ; Amentia ; Dementia ; extracellular ; 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 ; neuroprotection ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; Toxicities ; Toxic effect ; novel ; Reporting ; Modeling ; high throughput technology ; drug development ; High Throughput Assay ; high throughput screening ; develop software ; developing computer software ; software development ; neuropathology ; Intervention Strategies ; interventional strategy ; Intervention ; drug discovery ; Silent Mating Type Information Regulator 2-like Proteins ; Sir2-like Proteins ; Sirtuins ; µfluidic ; Microfluidics ; Causality ; causation ; disease causation ; Etiology ; FK506 Binding Protein 12-Rapamycin Associated Protein 1 ; FKBP12 Rapamycin Complex Associated Protein 1 ; FRAP1 ; FRAP2 ; Mechanistic Target of Rapamycin ; RAFT1 ; mTOR ; mammalian target of rapamycin ; FRAP1 gene ; Address ; global health ; Symptoms ; Recombinants ; in vivo ; Alzheimer's Disease Pathway ; follow-up ; Active Follow-up ; active followup ; follow up ; followed up ; followup ; Pathway interactions ; pathway ; pre-clinical ; preclinical ; preclinical study ; pre-clinical study ; age related ; age dependent ; age effect ; aging effect ; anti aging ; anti aging drug ; anti aging medicine ; antiaging ; antiaging drug ; antiaging medicine ; novel strategies ; new approaches ; novel approaches ; novel strategy ; Outcome ; innovation ; innovate ; innovative ; drug testing ; drug detection ; Alzheimer's disease risk ; Alzheimer risk factor ; alzheimer risk ; Alzheimer's disease model ; AD model ; alzheimer model ; healthy aging ; effective intervention ; FDA approved ; lead series ; drug candidate ; screening ; Drug Targeting ; in vivo imaging ; imaging in vivo ; cognitive ability ; Alzheimer's disease pathology ; AD pathology ; Alzheimer's pathology ; proteostasis ; protein homeostasis ; lead candidate ; microfluidic technology ; µfluidic technology ; in vivo monitoring ; Alzheimer's disease therapeutic ; Alzheimer's therapeutic ; Alzheimer's disease therapy ; Alzheimer's therapy ; Phase II/III Clinical Trial ; Phase 2/3 Clinical Trial ; drug repurposing ; repurposing agent ; repurposing medication ;