Plasma Assays for NPTX2 in Alzheimer's Disease

Abstract CogNext is submitting this proposal in response to PAR-19-316 to develop novel diagnostics for Alzheimer’s disease (AD). AD represents a major medical challenge and precedent from failed clinical trials with amyloid reducing therapies highlights the need for biomarkers that can predict progression of cognitive failure, and that are diagnostic and prognostic at the earliest stage of disease. CogNext Diagnostics was founded by neuroscientists from Johns Hopkins whose studies of the cellular and molecular basis of memory identified CSF NPTX2 to be a biomarker with extraordinary diagnostic performance. NPTX2 plays an essential role in the physiology of memory and is markedly decreased in brain and CSF of human subjects with AD. CSF NPTX2 correlates with cognitive performance in aged, non-demented individuals, distinguishes controls from MCI as well as Aß or tau, enhances the diagnostic performance of tau, and in two independent studies predicts progression of disease in MCI/early AD. A CSF assay for NPTX2 has been awarded patent protection and CogNext has an option for exclusive license. Here, CogNext seeks SBIR support to test the diagnostic performance of a new assay that detects NPTX2 in plasma. The assay specifically detects NPTX2 that is in close physical proximity to co-functional proteins and provides a novel indicator of NPTX2-dependent brain physiology that distinguishes individuals with MCI/AD from age-matched controls. In Aim 1, CogNext will work with a biotech partner to measure plasma NPTX2 in archived biospecimens collected as part of phase 2 and phase 3 clinical trials of an amyloid reducing therapy. Individuals selected for the phase 3 trail were assessed to be prodromal to early onset AD and are representative of future clinical trials that will seek to start therapy before the onset of manifest AD. CogNext and Biopharm partner will determine if plasma NPTX2 alone or in combination with extensive existing measures including CSF Aß, tau, PET-amyloid, and neuropsychiatic testing predicts progression. A plasma assay that could match the diagnostic performance of CSF NPTX2 has the potential to transform clinical trial design. Aim 2 will address the need for high quality monoclonal antibodies (mAbs) that specifically react with NPTX2 and co-functional proteins and that can be used to develop commercializable assays. Rabbit mAbs will be generated using state of the art B-cell selection and validated for specificity and utility for NPTX2 assays in CSF and plasma. CogNext will work with business partners in a direct-to-industry approach that offers that fastest path to commercialization and contribution to AD research.Project Narrative CogNext Diagnostics LLC has developed a CSF biomarker, NPTX2, that predicts progression of cognitive decline in early-stage Alzheimer’s disease (AD). In the present proposal, CogNext will work with a Biotech partner to validate the prognostic performance of a novel blood/plasma assay for NPTX2 by examining archived biospecimens from a large clinical trial that enlisted individuals with prodromal and early-stage AD. Additionally, CogNext will develop advanced reagents and assays for NPTX2 that can achieve commercialization.