Research Project
9555778
Alzheimer?s disease elicits progressive degeneration of cortical and limbic structures involved in learning and memory, cognition, executive control and emotions. Despite its devastating impact on individuals and its enormous national economic toll, there are no FDA-approved drugs that modify the disease process to stop or reverse Alzheimer?s disease progression. In this SBIR Phase I project, Spinogenix will perform critical tests of novel small molecules that have the unique ability to reverse a central aspect of Alzheimer?s disease pathogenesis: the loss of axospinous glutamatergic synapses. Synapse loss begins very early in Alzheimer?s disease, even before the appearance of the hallmark histopathological features of amyloid plaques and neurofibrillary tangles (NFTs), and it progresses in a manner that correlates more directly with cognitive decline than any other aspect of Alzheimer?s disease pathology. This loss of synapses is induced, to a large extent, by soluble oligomeric forms of beta amyloid peptides (A?). To thwart this progression, Spinogenix is developing a novel class of small molecules that bind A? oligomers and prevent their association with intracellular and extracellular targets implicated in Alzheimer?s disease pathogenesis. The initial members of this new class of A?-binding molecules (benzothiazole aniline (BTA/SPG10X) derivatives) were subsequently found to have potent spine-inducing activity in wild-type (WT) mouse neurons in vitro and in vivo. In addition, the compositions were able to rescue deficits in spine density and memory in a triple transgenic (3xTG) mouse model of Alzheimer?s disease. New derivatives of BTA structures ? benzothiazole amphiphiles (BAMs/ SPG20X) ? appear to maintain the mechanistic and functional features of earlier compositions but exhibit greater in vitro potency. Recently, it was found that SPG101 targets fascin, which may explain its spinogenic effect. The three specific aims of this project will provide a basis for aggressive, preclinical and clinical development of proprietary, third generation compositions for Alzheimer?s disease. In this project, Spinogenix will accelerate the pre-clinical development of BAM and BTA derivatives (SPG30X) that bind A?, target fascin and are spinogenic, reduce A? toxicity and increase dendritic spine density. This is an innovative approach to Alzheimer?s disease therapy because there has never been a drug targeting the loss of the dendritic spines and the accompanying loss of glutamatergic synapses. To achieve its goal of developing a small molecule therapeutic for Alzheimer?s disease, Spinogenix proposes three major studies: 1. Develop a detailed analysis of the pharmacological properties of the best BAM (SPG203) to understand how it can be improved. 2. Synthesize targeted aspects (e.g. metabolic stability or potency in binding to fascin) and screen the derivatives to establish a structure-activity relationship of the compounds with respect to A? binding and fascin targeting, and spinogenic activity. The goal is to identify compounds with better stability, enhanced A? binding affinity, improved spinogenic activity and an acceptable toxicity profile. The in vitro screens will establish compounds for further toxicity and pharmacokinetic testing in normal mice. 3. Characterize lead compound SPG30X- induced memory, cognition and spinogenesis in vivo in 3xTG AD mice using super-resolution imaging methods; spine density and shape will be analyzed both in regions affected and regions spared in Alzheimer?s disease. While pharmacology cannot compensate for lost synaptic connectivity that drives cognitive decline, it is anticipated that by increasing spine density and increasing functional synapses, SPG compounds may offer a transformative new monotherapy and synergistic co-therapy.
