Cognition Therapeutics Inc. (CogRx) has discovered CT1812, a novel oligomer receptor antagonist that is the only drug candidate demonstrated to prevent and displace binding of Abeta oligomers to receptors on brain cells. By stopping the initiating event in the Abeta oligomer cascade, this first-in?class drug candidate completely blocks downstream synaptotoxicity and restores memory to normal in aged transgenic mouse models of Alzheimer?s disease. CT1812 displaces receptor-bound Abeta oligomers by allosterically antagonizing the sigma-2/PGRMC1 receptor (Izzo et al., 2014a, b). CT1812 thus represents the first diseasemodifying therapeutic that will test the oligomer hypothesis of Alzheimer?s disease. Such a drug candidate would significantly impact the lives of the 35 million patients worldwide suffering from AD and MCI, for whom no disease-modifying treatment exists. This proposal seeks to identify biomarkers of CT1812 functional target engagement. The project proposes 1) measuring changes in expression levels of proteins regulated by sigma- 2/PGRMC1 in the presence of Abeta oligomers that are blocked by CogRx?s sigma-2/PGRMC1 antagonists in neurons and 2) determining if such changes are observed in the brains, CSF or serum of transgenic mice treated with CT1812. The proposed studies will also conduct unbiased proteomic investigations on biofluids from wild type and transgenic AD mice treated with CT1812 or vehicle to identify patterns of altered protein expression associated with drug engagement with target in settings of disease. With this data, we propose to construct a pathway from CT1812 target engagement to peripherally available biomarker using targeted reaction monitoring (MRM) proteomics data. The successful outcome of this project is the development of an assay to measure candidate biomarkers in humans for exploratory investigation in the clinic.

Public Health Relevance

Cognition Therapeutics Inc. has discovered a drug candidate that promises to stop and even reverse the memory loss in Alzheimer?s disease. This drug candidate, CT1812, works by a completely novel mechanism to stop the binding of toxic proteins that build up in the brains of Alzheimer?s patients known as Abeta oligomers. We 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 plasma. Such biomarkers would be invaluable for exploratory investigation of target engagement in the clinic of drug candidates in Alzheimer?s patients and would be a tool in the development of therapeutics which could significantly impact the lives of the 35 million patients worldwide suffering from Alzheimer?s disease and Mild Cognitive Impairment, for whom no disease-modifying treatment exists.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
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Special Emphasis Panel (ZRG1-ETTN-M (11)B)
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Refolo, Lorenzo
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Cognition Therapeutics, Inc.
Domestic for-Profits
United States
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