Discovery and validation of OMA1 inhibitors

Discovery and validation of OMAinhibitors ABSTRACTAccording to the Alzheimer s Associationmillion Americans are living with the diseasea number to reach almostmillion byAlzheimer s disease is theth leading cause of death in the United States and one in three seniors will die with dementiaThe costs associated with Alzheimer s mounted to $billion inand are expected to grow to as much as $trillion byYet we still have no therapies available to reversehalt or even decelerate neurodegeneration in patients with Alzheimer sAll available medicines only treat the symptoms of the diseasesuch as memory lossconfusiondepressionanxietyand sleep changesHence there remains a huge unmet medical need for disease modifying treatmentsespecially considering the rapidly increasing socio economic burden associated with Alzheimer s diseaseThe two neuropathological hallmarks of Alzheimer s disease are plaques and neurofibrillary tanglesHoweverAlzheimer s is a complex disease with many different contributing factorsnotably aging itself being a major risk factorNot surprisinglyclinical trials with amyloidand tau targeting therapies resulted only in marginal cognitive benefits for patients further emphasizing the need for novelalternativeand complementary approaches to treatmentBeginning ofthere weremedicines in clinical development and there is a shift towards nonamyloid mechanisms of action for drugs in earlier phases of drug developmentStillearly diagnosis and clinical trial design remain challenging for Alzheimer s diseaseWe have identified a novel molecular mechanism of action that is complementary to the existing treatment strategies for Alzheimer s diseaseOur central hypothesis is that the interplay of age related extracellular and intracellular alterationssuch as cerebrovascular changesthe formation of plaques and neurofibrillary tanglesand inflammationevoke a mitochondrial stress responsewhich entails activation of a critical proteaseThis protease regulates a rate limiting step of the apoptotic cell death cascadewhich results in outer membrane permeabilization and cytochrome c releaseFor phaseof this grantwe will initiate a drug discovery program for inhibitors of this proteaseThese agents will be useful tool compounds for in vivo proof of concept studiesMoreoverthese compounds will form the basis for a drug development program in phaseof this grant Discovery and validation of OMAinhibitors PROJECT NARRATIVETranslating basic research into therapies that eventually can help people still is a daunting taskWe have identified a novel point for medical intervention for patients with Alzheimer s diseaseThe overall goal of this grant proposal is to identify the first molecules that can intervene at this focal pointWe will validate these compounds and ensure they are specific and safeThese are the first steps in the complicated and tedious drug development processIf the here proposed research is successfulwe can progress with the pre clinical development in phaseof this grant application conducting safety and toxicology studies as well as pharmacodynamics and pharmacokinetics studiesIn due coursethese drugs can be tested in patients to see whether they really can stop or at least slow down the disease progression