The prevalence of Alzheimers disease (AD) is increasing worldwide due to demographic shifts and an aging population and currently there are no disease-modifying drugs. It is the most costly disease in the US with a financial burden of over $236 billion annually in direct costs that is estimated to increase to $1 trillion by 2050. There is an urgent unmet need for the development of blood biomarkers for the early detection and staging of AD. The lack of accurate, sensitive, and well-validated biomarkers for AD is a rate limiting factor for identifying effective treatments. Tau protein, and in particular tau oligomers, have become a high priority target for AD due to 1) their high correlation with diseased regions within the brain of AD patients, 2) their newly discovered extracellular activity that is believed to result in the impairment of synaptic function and loss of memory and 3) their role in the spread of pathology. Oligomerix has developed novel methods to highly purify tau oligomers and has discovered that they undergo autoproteolytic fragmentation at specific sites creating neo-epitopes at the cut ends. Polyclonal antibodies (pAbs) to the neo-epitopes were generated, and one pAb showed a striking specificity for AD specimens. In Aims 1 and 2, monoclonal Abs (mAbs) will be generated that have specificity for this fragment end and specificity for the uncut site. Aim 3 will be to characterize the mAbs and perform a proof-of-concept biomarker study. The overall goal of this project is to produce a blood-based, non-invasive diagnostic test as a biomarker for tau fragment levels from biological specimens for AD. These mAbs can also be used to understand the role of tau autoproteolytic fragmentation in AD, and the ratio of cut to uncut tau at this site may provide greater sensitivity in determining AD stage. Additionally, the tau fragment specific mAb that will be developed under the proposed program could have tremendous commercial utility for any therapeutic program, immuno- or small molecule therapeutics seeking to reduce tau accumulation, enhance clearance, or prevent the formation of tau oligomers. The global CNS biomarker market is projected to reach $5.1 billion by 2020 from $3.1 billion in 2015. The proposed study will be enabling for Oligomerixs internal drug discovery programs, and the Company will make these assays available by commercializing them via collaboration with a diagnostic or life sciences company. Thus the proposed program, if successful, will have significant commercial potential and impact. The strong management and scientific team will ensure competencies in mAb production and characterization, as well as assay development and commercialization. Furthermore, the presence of Dr. Peter Davies and Dr. Steven Jacobsen on the Scientific Advisory Board provide top notch scientific and business experience to the Company.
Public Health Relevance Statement: PROJECT NARRATIVE There is an unmet need for the development of blood biomarkers for early detection of Alzheimers disease (AD). A blood-based biomarker would enable more rapid patient recruitment and better retention for clinical therapeutic and diagnostic studies because it is minimally invasive, low cost, and easier to perform. The overall goal of this project is to produce a blood-based, non-invasive diagnostic test as a biomarker for tau fragment levels from biological specimens for Alzheimers disease (AD).
Project Terms: aging population; alzheimer disease detection; Alzheimer's Disease; Antibodies; assay development; base; Biological; Biological Assay; Biological Markers; Biological Sciences; Blood; blood-based biomarker; Brain; Brain Diseases; brain tissue; Businesses; Cerebrospinal Fluid; Cleaved cell; Clinical; Collaborations; commercialization; Competence; cost; Cost of Illness; Development; Diagnostic; Diagnostic tests; Direct Costs; Disease; Disease Progression; drug development; drug discovery; early detection biomarkers; effective therapy; Employee Strikes; Ensure; Enzyme-Linked Immunosorbent Assay; Epitopes; experience; extracellular; Goals; Hybridomas; Immunoblotting; Immunohistochemistry; Immunotherapeutic agent; Impairment; in vivo; Laboratories; Legal patent; Liquid substance; loss of function; Memory Loss; Methods; minimally invasive; N-terminal; noninvasive diagnosis; notch protein; novel; Pathologic; Pathology; Patient Recruitments; Patients; Pattern; Peptides; Pharmaceutical Preparations; Phase; phase 1 study; Plasma; polyclonal antibody; Prevalence; prevent; Production; programs; Proteins; Recombinants; Reproducibility; Research; Role; Signal Transduction; Site; Small Business Innovation Research Grant; small molecule therapeutics; Specificity; Specimen; Staging; Structure; success; Surrogate Markers; synaptic function; tau aggregation; tau Proteins; Therapeutic; Therapeutic Studies; Therapeutic Uses
