A Novel Small Molecule TNF-alpha Inhibitor as a Disease-Modifying Alzheimer's Disease Drug Treatment

ABSTRACT The goal of this proposal is to develop tumor necrosis factorTNFinhibiting compounds as neuroprotectant drugs for treating Alzheimer s diseaseADCurrent FDA approved AD interventions are symptomatic treatments with limited efficacy which do not affect AD etiology or modify the course of disease progressionThusa critical need exists for a novel AD treatment directed towards AD pathophysiologyRecent studies implicate the neuroinflammatory cytokine TNFas a key mediator in ADassociated neurodegenerative pathologyMultiple preclinical and clinical studies indicate that TNFis adruggablemolecular target to modify the course of AD progressionPreliminary Studies demonstrate that our lead compound shows potent TNFinhibition in vitroOur PhaseSBIR studies demonstrate that our small molecule TNFinhibitor administered orally every day formonths significantly improved cognitive function in the triple transgenicxTgAD mouse modelOur compound also modulated brain TNFprotein levels and halted the progress of AD associated neuropathology including Aplaques and neurofibrillary tangles as assessed by immunohistological stainingNo morbiditymortality or any obvious side effects were observed despite the long term oral daily treatment regimen with our compoundTaken togetherthese data strongly suggest that our lead compound is an excellent anti AD drug candidateThe proposed studies are following up on recently awarded phaseSBIR where we are performing several key FDA required IND studiesThe proposed CRP grant studies will build on the phaseSBIR studies to lead to an IND submissionKey Aims include large animal safety toxicology studies and preparation for Pre IND meeting with the FDA PROJECT NARRATIVE Alzheimer s DiseaseADis a significant neurological problem affecting nearlymillion of our senior U ScitizensThe present research aims to develop a compound that targets the underlying neuroinflammation in AD to modify disease progression and improve cognitive function