A Novel Small molecule TNF-alpha inhibitor as a disease-modifying AD drug treatment.

DESCRIPTION provided by applicant The goal of this proposal is to develop tumor necrosis factor a TNFa inhibiting compounds as neuroprotectant drugs for treating Alzheimerandapos s disease AD Current FDA approved AD interventions are symptomatic treatments with limited efficacy which do not affect AD etiology or modify the course of disease progression Thus a critical need exists for a novel AD treatment directed towards AD pathophysiology Recent studies implicate the neuroinflammatory cytokine TNF a as a key mediator in AD associated neurodegenerative pathology Multiple preclinical and clinical studies indicate that TNFa is a andquot druggableandquot molecular target to modify the course of AD progression Preliminary Studies demonstrate that our lead compound IDT shows potent TNFa inhibition in vitro Our Phase SBIR studies demonstrate that a low dose of IDT administered orally every day for months significantly improved cognitive function in the triple transgenic xTg AD mouse model IDT also modulated brain TNFa protein levels and halted the progress of AD associated neuropathology including A plaques and neurofibrally tangles as assessed by immunohistological staining No morbidity mortality or any obvious side effects were observed despite the long term oral daily treatment regimen with IDT Taken together these data strongly suggest that our lead compound is an excellent anti AD drug candidate The proposed Phase SBIR studies are designed to achieve two goals First we want to conduct the FDA safety and toxicology studies required for submission of IDT as an Investigational New Drug IND application which would allow its use in humans when approved Aims Second our efficacy data suggests IDT may be more effective at an even lower dose Aim will optimize IDT dose efficacy response at lower doses in xTgAD mice Aim Assess IDT genotoxicity Aim Assess IDT absorption distribution metabolism and excretion ADME Aim Assess oral IDT safety pharmacology in three studies Aim Assess repeated IDT dose toxicity in rats Aim Assess lower IDT doses in xTg AD mice PUBLIC HEALTH RELEVANCE Alzheimerandapos s Disease AD is a significant neurological problem affecting million of our senior U S citizens The present research aims to develop a compound that targets the underlying neuroinflammation in AD to modify disease progression and improve cognitive function