This grant will seek to develop a methodology that will allow us to test whether a promising new class of drugs for Alzheimer's disease is having the desired effect in the human brain. This methodology will allow pharmaceutical companies to make informed decisions about which drugs to advance into late stage clinical trials, and to optimize dosing and administration schedules based on pharmacodynamic response. C2N Diagnostics has licensed the platform technology from Washington University to carry out the company's stable isotope labeling kinetic (SILK) assay. This assay is used to measure production and clearance rates of proteins in the brain. Previously, this methodology has been applied to measuring production and clearance of total A2 from the brain, and evaluating the biologic activity of certain compounds in clinical development for the treatment of Alzheimer's. To measure the biologic activity of an emerging class of compounds, gamma-secretase modulators, we need to be able to measure the production and clearance of the individual A2 isoforms, specifically A2 38, 40 and 42. The experiments proposed in this grant will develop this methodology in Phase I of this grant. In Phase II, the methodology will be applied to a small patient study. Applying the technology to a proof of concept human study will greatly facilitate commercialization of the technology. Further, this technology will greatly enhance our understanding of how AD metabolism plays a role in the pathogenesis of the disease.
Public Health Relevance: Alzheimer's disease is a growing problem with an estimated 5 million people currently affected in the US. There are currently no disease modifying drugs approved for AD, in part due to a paucity of relevant tools to measure biologic activity and clinical efficacy for these types of drugs. The proposed experiments are intended to allow C2N to help pharmaceutical companies optimize the quality of their drug development efforts and to expedite bringing promising disease modifying treatments to the clinic.
Public Health Relevance Statement: 7. Project Narrative Alzheimer's disease is a growing problem with an estimated 5 million people currently affected in the US. There are currently no disease modifying drugs approved for AD, in part due to a paucity of relevant tools to measure biologic activity and clinical efficacy for these types of drugs. The proposed experiments are intended to allow C2N to help pharmaceutical companies optimize the quality of their drug development efforts and to expedite bringing promising disease modifying treatments to the clinic.
Project Terms: ADAM10 protein; Abnormal Assessment of Metabolism; Affect; Age; Alzheimer; Alzheimer beta-Protein; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's Disease; Alzheimer's amyloid; Alzheimers Dementia; Alzheimers disease; Amino Acids; Amyloid A4 Protein Precursor; Amyloid Alzeheimer's Dementia Amyloid Protein; Amyloid Beta-Peptide; Amyloid Fibril Protein (Alzheimer's); Amyloid Plaques; Amyloid Protein A4; Amyloid Protein Precursor; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid beta-Protein, Alzheimer's; Animal Model; Animal Models and Related Studies; Arm; Assay; Behavior; Behavioral; Bioassay; Biologic Assays; Biological Assay; Blood; Blood Plasma; Brain; C-terminal; Cell Culture System; Cells; Central Nervous System; Cerebrospinal Fluid; Cleaved cell; Clinic; Clinical; Clinical Trials; Clinical Trials, Phase I; Clinical Trials, Phase II; Clinical Trials, Phase III; Clinical Trials, Unspecified; Clinical assessments; Cognitive; Communities; Complex Mixtures; Confidential Information; Cost Sharing; Culture Media; Cultured Cells; Data; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Development; Development and Research; Diagnostic; Diagnostic tests; Disease; Disorder; Dose; Drug effect disorder; Drugs; ELISA; Early-Stage Clinical Trials; Encephalon; Encephalons; Enzyme-Linked Immunosorbent Assay; Evaluation; Feasibility Studies; Future; Government; Grant; Hand; Hour; Human; Human, General; Immune Precipitation; Immunoprecipitation; Individual; Infusion; Infusion procedures; Intermediary Metabolism; Isoforms; Kinetic; Kinetics; L-Leucine; Label; Lead; Left; Legal patent; Leucine; Leucine, L-Isomer; Licensing; METBL; MT-bound tau; Man (Taxonomy); Man, Modern; Measures; Medication; Metabolic Clearance Rate; Metabolic Processes; Metabolic Studies; Metabolism; Metabolism Studies; Method LOINC Axis 6; Methodology; Methods; N-terminal; NH2-terminal; Nervous System, Brain; Nervous System, CNS; Neuraxis; Neuritic Plaques; Neurofibrillary Tangles; Noise; Patents; Pathogenesis; Patients; Pb element; Peptides; Persons; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Preparations; Pharmaceuticals; Pharmacodynamics; Pharmacologic Substance; Pharmacological Substance; Phase; Phase 1 Clinical Trials; Phase 2 Clinical Trials; Phase 3 Clinical Trials; Phase I Clinical Trials; Phase I Study; Phase II Clinical Trials; Phase III Clinical Trials; Plasma; Play; Population; Position; Positioning Attribute; Primary Senile Degenerative Dementia; Production; Programs (PT); Programs [Publication Type]; Protein Cleavage; Protein Isoforms; Proteins; Proteolysis; Quality Control; R & D; R&D; Relative; Relative (related person); Reliance; Research Contracts; Reticuloendothelial System, Blood; Reticuloendothelial System, Serum, Plasma; Role; SBIR; SBIRS (R43/44); SCHED; Saints; Sampling; Schedule; Scientist; Senile Plaques; Serum, Plasma; Services; Site; Small Business Innovation Research; Small Business Innovation Research Grant; Specificity; Stable Isotope Labeling; Staging; Technology; Testing; Time; Universities; Upper arm; Validation; Variant; Variation; Washington; Work; a beta peptide; abeta; abeta accumulation; abeta aggregation; abstracting; aminoacid; amyloid beta; amyloid beta accumulation; amyloid beta aggregation; amyloid beta plaque; amyloid precursor protein; amyloid-b plaque; amyloid-b protein; base; beta amyloid fibril; beta secretase; biomarker; clearance rate; cleaved; clinical efficacy; clinical investigation; commercialization; cored plaque; dementia of the Alzheimer type; design; designing; diffuse plaque; disease control; disease/disorder; disorder control; drug action; drug candidate; drug development; drug/agent; experience; experiment; experimental research; experimental study; gamma secretase; gamma secretase complex; gene product; growth media; heavy metal Pb; heavy metal lead; human study; human subject; improved; in vivo; inhibitor; inhibitor/antagonist; instrument; interest; intervention development; mass spectrometer; measurement of metabolism; metabolic abnormality assessment; metabolomics; microtubule associated protein tau; microtubule bound tau; microtubule-associated protein tau; microtubule-bound tau; model organism; neurofibrillary degeneration; neurofibrillary lesion; neurofibrillary pathology; novel; phase 1 study; phase 1 trial; phase 2 study; phase 2 trial; phase 3 study; phase 3 trial; phase I trial; phase II trial; phase III trial; point-of-care diagnostics; preclinical study; prevent; preventing; primary degenerative dementia; programs; protocol, phase I; protocol, phase II; protocol, phase III; research and development; research study; response; senile dementia of the Alzheimer type; social role; soluble amyloid precursor protein; spinal fluid; stable isotope; study, phase II; study, phase III; success; tangle; tau; tau Proteins; tau factor; therapy development; tissue/cell culture; tool; treatment development; treatment trial
