PROGENRA INC — Department of Health and Human Services SBIR Phase I: NIA

Description

DESCRIPTION provided by applicant Alzheimerandapos s disease AD affects an estimated million people worldwide this number is predicted to double in the next decade AD results from the degeneration and death of neurons in the hippocampus and the entorhinal cortex regions of the brain areas that are critical for learning and memory Patients in end stage AD lose the ability to perform basic bodily functions such as walking and swallowing and require round the clock care Ultimately fatal with no cure available AD is the sixth leading cause of death in the United States Current therapeutics which provide temporary symptomatic relief only in patients with early stage AD have serious side effects and cannot prevent neuronal death and disease progression Thus it is necessary to identify novel therapeutics that can actually halt the progression of AD Microscopic evidence has associated mitochondrial damage and the appearance of autophagic vacuoles with the onset of AD Moreover evidence suggests that mitophagy a regulatory form of autophagic degradation which is mediated by the kinase PINK and the ubiquitin E ligase Parkin and which normally eliminates dysfunctional mitochondria is overwhelmed and becomes inadequate to prevent accumulation of damaged mitochondria in AD affected neurons These results support the notion that activation of Parkin the key element of mitophagy is a promising therapeutic avenue that will act by enhancing compromised mitophagy in AD patients Overexpression of Parkin in the AD mouse model APPswe PSEN E ameliorates AD related symptoms and restores mitochondrial integrity Parkin exists in an auto inhibited andapos offandapos state in the cytosol via multiple intramolecular interactins genetic disruption of these interactions stimulates Parkin activity and promotes its translocation to dysfunctional mitochondria The goal of the present project is to mimic this effect with small molecules that activate Parkin by relieving Parkin auto inhibition thereby promoting mitophagy Such activators are expected to prevent the mitophagy deficiency induced neuronal death and consequently to hinder the progression of AD A TR FRET based homogeneous E assay will be utilized to conduct high throughput screening HTS of a diversity based and targeted small molecule library to identify potent and selective activators of Parkin Subsequently cellular proo of concept assays will be performed to measure the impact of the small molecule agonists on Parkin activation and mitophagy improvement In Phase II preclinical development will be pursued employing chemical optimization and efficacy ADME studies using relevant animal models The ultimate commercial goal is the development of a novel small molecule agonist that can be used to stop the progress of AD PUBLIC HEALTH RELEVANCE Alzheimerandapos s Disease AD is devastating in terms of mortality morbidity emotional strain and cost There is currently no cure approved treatments address symptoms but lose efficacy over time and do not prevent neuronal death the root cause of the disease In the proposed project activators of Parkin an enzyme from the ubiquitin pathway which helps to remove damaged mitochondria associated with neuronal cell death will be identified and in Phase II tested for their ability to stop the progression of symptoms of AD in an animal model