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 every day for 10 months significantly improved cognitive function in the triple-transgenic (3xTg) AD mouse model. Our compound also modulated brain TNF? protein levels and halted the progress of AD-associated neuropathology including A plaques and neurofibrillary tangles as assessed by immunohistological staining. No morbidity, mortality or any obvious side effects were observed despite the 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 studies are following up on recently awarded phase 2 SBIR where we are performing several key FDA-required IND studies. The proposed CRP grant studies will build on the phase 2 SBIR studies to lead to an IND submission.
Key Aims i nclude large animal safety toxicology studies and preparation for Pre-IND meeting with the FDA.

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)
Project #
2SB1AG051302-04
Application #
9466541
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Refolo, Lorenzo
Project Start
2015-09-01
Project End
2020-05-31
Budget Start
2017-09-15
Budget End
2018-05-31
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
P2, Inc.
Department
Type
DUNS #
182472162
City
Cincinnati
State
OH
Country
United States
Zip Code
45242