The goal of this proposal is to develop tumor necrosis factor ? (TNF?)-inhibiting compounds as neuroprotectant drugs for treating Alzheimer?s disease (AD). Current FDA-approved AD interventions are symptomatic treatments with limited efficacy which do not affect AD etiology or modify the course of disease progression. Thus, a critical need exists for a novel AD treatment directed towards AD pathophysiology. Recent studies implicate the neuroinflammatory cytokine TNF-? as a key mediator in AD- associated neurodegenerative pathology. Multiple preclinical and clinical studies indicate that TNF? is a ?druggable? molecular target to modify the course of AD progression. Preliminary Studies demonstrate that our lead compound shows potent TNF? inhibition in vitro. Our Phase 1 SBIR studies demonstrate that our small molecule TNF? inhibitor administered orally or peripherally significantly improved cognitive function in multiple AD mouse models. Our compound also modulated brain TNF? protein levels, microglial activation, and the progress of AD-associated neuropathology. No morbidity, mortality or any obvious side effects were observed despite long-term oral daily treatment regimen with our compound. Taken together, these data strongly suggest that our lead compound is an excellent anti-AD drug candidate. The proposed SBIR phase 2 grant studies will de-risk further development of our compound by 1) finding a new synthetic method that is viable for commercial manufacturing and 2) performing key early safety toxicology studies in preparation for future FDA-required IND enabling studies.

Public Health Relevance

Alzheimer?s Disease (AD) is a significant neurological problem affecting nearly 5 million of our senior U.S. citizens. The present research aims to develop a compound that targets the underlying neuroinflammation in AD to modify disease progression and improve cognitive function.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
5R44AG044958-03
Application #
9785351
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Martin, Zane
Project Start
2013-08-15
Project End
2021-06-30
Budget Start
2019-08-01
Budget End
2021-06-30
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
P2, Inc.
Department
Type
DUNS #
182472162
City
Cincinnati
State
OH
Country
United States
Zip Code
45242