Alzheimer's disease (AD) is a neurodegenerative disorder that leads to the progressive loss of memory and other cognitive functions. At this time, there are no approved treatments that are capable of delaying its onset or slowing its progression. We have developed a novel category of drug-like, small molecule compounds that specifically target a cell surface receptor that is expressed by neurons affected in AD, known as the p75 receptor. These p75 receptor ligands activate survival-promoting signaling and inhibit degenerative-promoting signaling of the p75 receptor. In tissue culture studies, these ligands are capable of blocking the ability of amyloid beta (A?) to activate degenerative signaling within neurons affected in AD. The protective effects of these compounds occur at low nanomolar concentrations and have been verified to occur through their action at p75. Moreover, our ligands block the toxicity of A? oligomers, the A? species thought to be most toxic to neurons and most relevant to AD. In studies of normal middle aged mice, our lead compound has been demonstrated to reach the brain following daily oral administration and has been found to have no toxic effects including studies of hepatic, cardiac and DNA toxicity. In these mice, our lead compound demonstrates a significant neurotrophic effect of reversing or preventing basal forebrain cholinergic atrophy of the type that occurs during aging and AD in both human and rodent systems. In pilot trials in a well characterized AD mouse model, our lead compound appears to be improving memory function and to be reducing pathological features typical of AD. In this application we will complete the following three milestone-driven projects: i) verification of efficacy in Alzheimer's mice and assessment of potential mechanism-based side effects;ii) cGMP scaled up synthesis and purity necessary for an Investigational New Drug (IND) application to the FDA;and iii)toxicology and pharmacology studies designed to complete an IND application. Completion of these three projects will allow an IND application with the overall goal of obtaining IND approval for conducting the first Phase I trials humans. Completion of the proposed project will also establish a new chemical entity (NCE) and a novel, first in class, drug compound for development in AD therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01AG032225-05S1
Application #
8441845
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Petanceska, Suzana
Project Start
2007-09-30
Project End
2012-08-31
Budget Start
2012-03-15
Budget End
2012-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$100,000
Indirect Cost
Name
Stanford University
Department
Neurology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305