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.
|Nguyen, Thuy-Vi V; Shen, Lin; Vander Griend, Lilith et al. (2014) Small molecule p75NTR ligands reduce pathological phosphorylation and misfolding of tau, inflammatory changes, cholinergic degeneration, and cognitive deficits in A?PP(L/S) transgenic mice. J Alzheimers Dis 42:459-83|
|Simmons, Danielle A; Knowles, Juliet K; Belichenko, Nadia P et al. (2014) A small molecule p75NTR ligand, LM11A-31, reverses cholinergic neurite dystrophy in Alzheimer's disease mouse models with mid- to late-stage disease progression. PLoS One 9:e102136|
|Knowles, Juliet K; Simmons, Danielle A; Nguyen, Thuy-Vi V et al. (2013) Small molecule p75NTR ligand prevents cognitive deficits and neurite degeneration in an Alzheimer's mouse model. Neurobiol Aging 34:2052-63|
|Longo, Frank M; Massa, Stephen M (2013) Small-molecule modulation of neurotrophin receptors: a strategy for the treatment of neurological disease. Nat Rev Drug Discov 12:507-25|