Novel small molecules that target Alzheimer's disease by increasing spinogenesis and decreasing A-beta toxicity

Alzheimer s disease elicits progressive degeneration of cortical and limbic structures involved in learning and memorycognitionexecutive control and emotionsDespite its devastating impact on individuals and its enormous national economic tollthere are no FDA approved drugs that modify the disease process to stop or reverse Alzheimer s disease progressionIn this SBIR Phase I projectSpinogenix will perform critical tests of novel small molecules that have the unique ability to reverse a central aspect of Alzheimer s disease pathogenesisthe loss of axospinous glutamatergic synapsesSynapse loss begins very early in Alzheimer s diseaseeven before the appearance of the hallmark histopathological features of amyloid plaques and neurofibrillary tanglesNFTsand it progresses in a manner that correlates more directly with cognitive decline than any other aspect of Alzheimer s disease pathologyThis loss of synapses is inducedto a large extentby soluble oligomeric forms of beta amyloid peptidesATo thwart this progressionSpinogenix is developing a novel class of small molecules that bind Aoligomers and prevent their association with intracellular and extracellular targets implicated in Alzheimer s disease pathogenesisThe initial members of this new class of Abinding moleculesbenzothiazole anilineBTA SPGXderivativeswere subsequently found to have potent spine inducing activity in wild typeWTmouse neurons in vitro and in vivoIn additionthe compositions were able to rescue deficits in spine density and memory in a triple transgenicxTGmouse model of Alzheimer s diseaseNew derivatives of BTA structuresbenzothiazole amphiphilesBAMsSPGXappear to maintain the mechanistic and functional features of earlier compositions but exhibit greater in vitro potencyRecentlyit was found that SPGtargets fascinwhich may explain its spinogenic effectThe three specific aims of this project will provide a basis for aggressivepreclinical and clinical development of proprietarythird generation compositions for Alzheimer s diseaseIn this projectSpinogenix will accelerate the pre clinical development of BAM and BTA derivativesSPGXthat bind Atarget fascin and are spinogenicreduce Atoxicity and increase dendritic spine densityThis 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 synapsesTo achieve its goal of developing a small molecule therapeutic for Alzheimer s diseaseSpinogenix proposes three major studiesDevelop a detailed analysis of the pharmacological properties of the best BAMSPGto understand how it can be improvedSynthesize targeted aspectse gmetabolic stability or potency in binding to fascinand screen the derivatives to establish a structure activity relationship of the compounds with respect to Abinding and fascin targetingand spinogenic activityThe goal is to identify compounds with better stabilityenhanced Abinding affinityimproved spinogenic activity and an acceptable toxicity profileThe in vitro screens will establish compounds for further toxicity and pharmacokinetic testing in normal miceCharacterize lead compound SPGXinduced memorycognition and spinogenesis in vivo inxTG AD mice using super resolution imaging methodsspine density and shape will be analyzed both in regions affected and regions spared in Alzheimer s diseaseWhile pharmacology cannot compensate for lost synaptic connectivity that drives cognitive declineit is anticipated that by increasing spine density and increasing functional synapsesSPG compounds may offer a transformative new monotherapy and synergistic co therapy Currently approved drugs for Alzheimer s disease can slow its progressionbut cannot halt or reverse the destruction of synapses that cause the loss of memory experienced by patientsThis Phase I SBIR will identify a lead compound from a novel class of drugs that can protect neurons from toxic molecules and stimulate the brain to replace the synapses destroyed by Alzheimer s diseasethus providing a breakthrough in the treatment of this devastating illness