Target Engagement Biomarkers for Alzheimer's Therapeutics

AbstractProject Summary Cognition Therapeutics IncCogRxhas discovered CTa novel oligomer receptor antagonist that is the only drug candidate demonstrated to prevent and displace binding of Abeta oligomers to receptors on brain cellsBy stopping the initiating event in the Abeta oligomer cascadethis first in class drug candidate completely blocks downstream synaptotoxicity and restores memory to normal in aged transgenic mouse models of Alzheimerandapos s diseaseCTdisplaces receptor bound Abeta oligomers by allosterically antagonizing the sigmaPGRMCreceptorIzzo et alabCTthus represents the first diseasemodifying therapeutic that will test the oligomer hypothesis of Alzheimerandapos s diseaseSuch a drug candidate would significantly impact the lives of themillion patients worldwide suffering from AD and MCIfor whom no disease modifying treatment existsThis proposal seeks to identify biomarkers of CTfunctional target engagementThe project proposesmeasuring changes in expression levels of proteins regulated by sigmaPGRMCin the presence of Abeta oligomers that are blocked by CogRxandapos s sigmaPGRMCantagonists in neurons anddetermining if such changes are observed in the brainsCSF or serum of transgenic mice treated with CTThe proposed studies will also conduct unbiased proteomic investigations on biofluids from wild type and transgenic AD mice treated with CTor vehicle to identify patterns of altered protein expression associated with drug engagement with target in settings of diseaseWith this datawe propose to construct a pathway from CTtarget engagement to peripherally available biomarker using targeted reaction monitoringMRMproteomics dataThe successful outcome of this project is the development of an assay to measure candidate biomarkers in humans for exploratory investigation in the clinic Project Narrative Cognition Therapeutics Inchas discovered a drug candidate that promises to stop and even reverse the memory loss in Alzheimerandapos s diseaseThis drug candidateCTworks by a completely novel mechanism to stop the binding of toxic proteins that build up in the brains of Alzheimerandapos s patients known as Abeta oligomersWe are requesting funding support to identify and develop a target engagement biomarker through determination of precise measurements of biomarker proteins in biofluids such as CSF and plasmaSuch biomarkers would be invaluable for exploratory investigation of target engagement in the clinic of drug candidates in Alzheimerandapos s patients and would be a tool in the development of therapeutics which could significantly impact the lives of themillion patients worldwide suffering from Alzheimerandapos s disease and Mild Cognitive Impairmentfor whom no disease modifying treatment exists