SBIR-STTR Award

Discovery and validation of OMA1 inhibitors ABSTRACT According to the Alzheimer’s Association 5.7 million Americans are living with the disease, a number to reach almost 14 million by 2050. Alzheimer’s disease is the 6th leading cause of death in the United States and one in three seniors will die with dementia. The costs associated with Alzheimer’s mounted to $232 billion in 2017 and are expected to grow to as much as $1,1 trillion by 2050. Yet we still have no therapies available to reverse, halt or even decelerate neurodegeneration in patients with Alzheimer’s. All available medicines only treat the symptoms of the disease, such as memory loss, confusion, depression, anxiety, and sleep changes. Hence there remains a huge unmet medical need for disease modifying treatments, especially considering the rapidly increasing socio-economic burden associated with Alzheimer’s disease. The two neuropathological hallmarks of Alzheimer’s disease are plaques and neurofibrillary tangles. However, Alzheimer’s is a complex disease with many different contributing factors, notably aging itself being a major risk factor. Not surprisingly, clinical trials with amyloid-β and tau targeting therapies resulted only in marginal cognitive benefits for patients further emphasizing the need for novel, alternative, and complementary approaches to treatment. Beginning of 2018 there were 112 medicines in clinical development and there is a shift towards nonamyloid mechanisms of action for drugs in earlier phases of drug development. Still, early diagnosis and clinical trial design remain challenging for Alzheimer’s disease. We have identified a novel molecular mechanism of action that is complementary to the existing treatment strategies for Alzheimer’s disease. Our central hypothesis is that the interplay of age-related extracellular and intracellular alterations, such as cerebrovascular changes, the formation of plaques and neurofibrillary tangles, and inflammation, evoke a mitochondrial stress response, which entails activation of a critical protease. This protease regulates a rate-limiting step of the apoptotic cell death cascade, which results in outer membrane permeabilization and cytochrome c release. For phase 1 of this grant, we will initiate a drug discovery program for inhibitors of this protease. These agents will be useful tool compounds for in vivo proof of concept studies. Moreover, these compounds will form the basis for a drug development program in phase 2 of this grant.

Public Health Relevance Statement:
Discovery and validation of OMA1 inhibitors PROJECT NARRATIVE Translating basic research into therapies that eventually can help people still is a daunting task. We have identified a novel point for medical intervention for patients with Alzheimer’s disease. The overall goal of this grant proposal is to identify the first molecules that can intervene at this focal point. We will validate these compounds and ensure they are specific and safe. These are the first steps in the complicated and tedious drug development process. If the here proposed research is successful, we can progress with the pre-clinical development in phase 2 of this grant application conducting safety and toxicology studies as well as pharmacodynamics and pharmacokinetics studies. In due course, these drugs can be tested in patients to see whether they really can stop or at least slow down the disease progression.

Project Terms:
age related; Aging; Alzheimer's Disease; American; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Anxiety; Apoptosis; Apoptotic; Applications Grants; base; Basic Science; biological adaptation to stress; Biological Assay; Biological Availability; Brain; Cause of Death; Cell Death; Cell model; Cells; Cellular Stress; cerebrovascular; Chemicals; Chimeric Proteins; clinical development; Clinical Trials; Clinical Trials Design; cognitive benefits; Collection; Complement; Complex; Confusion; cost; cytochrome c; Data; Dementia; Development; Disease; Disease Progression; Dose; drug development; drug discovery; Drug effect disorder; Drug Targeting; Early Diagnosis; Economic Burden; Eligibility Determination; Ensure; Exhibits; extracellular; FDA approved; Functional disorder; Goals; Grant; high throughput screening; Homeostasis; Impaired cognition; in vivo; Inflammation; inhibitor/antagonist; Inner mitochondrial membrane; Intervention; Kidney Failure; Knock-out; Libraries; Mediating; Medical; Medicine; Membrane; Memory Loss; Mental Depression; Mitochondria; Modeling; Molecular Mechanisms of Action; Morphology; mutant; Myocardial Infarction; Nerve Degeneration; Neurofibrillary Tangles; neuron loss; Neuroprotective Agents; novel; OPA1 gene; Optic Nerve; Organelles; Patients; Peptide Hydrolases; Pharmaceutical Preparations; pharmacokinetics and pharmacodynamics; Pharmacology; Pharmacotherapy; Phase; preclinical development; Predisposition; presenilin-1; prevent; Process; Program Development; programs; prohibitin; Protease Inhibitor; protein aminoacid sequence; Proteins; Protocols documentation; Quality Control; Recycling; repaired; Research; resilience; response; Risk Factors; Running; Safety; Site; Sleep; Small Business Innovation Research Grant; small molecule; small molecule inhibitor; Societies; socioeconomics; Specificity; Specimen; Stress; symptom treatment; targeted treatment; tau Proteins; Tauopathies; Testing; tool; Toxicology; Transgenic Mice; Translating; treatment strategy; Unite