Amyloid-Beta and Tau/Glycosaminoglycan Dual Inhibitor for Alzheimer's Disease

ABSTRACT The aim of this project is to support an IND application for GTC-3295 for the treatment of Alzheimer's Disease (AD). Neurodegenerative amyloid diseases such as AD have common underlying biochemical pathways leading to oligomerization and aggregation of amyloidogenic peptides and prion-like spreading of amyloid proteopathic seeds throughout the Central Nervous System (CNS). Recent data suggest that heparan sulfate glycosaminoglycans (HS-GAGs) are the receptors responsible for internalization and spreading of amyloid-beta (Abeta) and tau neuropathologies in the brain. We are developing a novel class of therapeutics, Glycosaminoglycan-Interacting Small Molecules (GISMOs), for the treatment of AD. GISMOs are drug-like small molecule compounds that inhibit Abeta and tau interactions with HS-GAGs, each of which is a key molecule implicated in AD pathogenesis, and may reduce propagation of these aggregated proteins in the Alzheimer's brain. GTC-3295 is a New Chemical Entity (NCE) and has dual activity as it efficiently inhibits both Abeta as well as Tau interactions with HS- GAGs. In previous studies in a transgenic mouse model of AD, GTC-3295 decreased amyloid burden in the mouse brain by as much as five-fold, and significantly decreased hyperphosphorylated tau levels in CA1 region of hippocampus. Initial preclinical studies indicate that GTC-3295 is an orally available and brain penetrant compound possessing favorable properties in in vitro ADME, pharmacokinetics, toxicity and other studies. These results provide justification to continue developing GTC-3295. In this SBIR project, we will perform a number of IND-enabling preclinical studies including GLP Toxicology studies in two species, scale-up synthesis, formulation studies, and development of bioanalytical methods. We will also evaluate efficacy of GTC-3295 in two transgenic models of AD, that separately address Abeta and tau neuropathologies. Completion of these requisite development activities should position this project towards a successful IND submission to the FDA and advancing into Phase I clinical trials in humans.