Alzheimerâs Disease (AD) is a common and devastating disease affecting over 25 million patients worldwide. AD patients lose their independence and are in need of constant care, which costs estimate above $250B in the US alone. AD is considered a graveyard for therapeutic programs with success rate of 0.5%, an order of magnitude lower than the ~5% industry average. Even successful therapeutics offer only moderate symptomatic relief and do not halt diseases progression. We believe that a main reason for the repeated failures is the lack of a diagnostic toolbox enabling early detection, before clinical symptoms appear and neurons already lost, selection of patients with more homogeneous pathology and routine monitoring of treatment response. NeuroDex aims to develop a blood-test that allows rapid, accurate and robust population screening for early detection and frequent monitoring of treatment response. This test is based on immune-purification of Neuronal-Derived Exosomes (NDE) from plasma samples. Exosomes are small vesicles secreted from all cells while containing a sample of their parent cell proteins and RNA signature. Thus, capturing NDE provide a surrogate sample of brain neurons of a leaving individual. A prototype of the test was already shown to distinguish between AD and controls, as well as Frontotemporal Dementia (FTD), common dementia, with over 95% specificity and sensitivity. Moreover, using samples from 931 person-visits in Baltimore Longitudinal Study on Aging (BLSA) showed that the test predicted AD development up to 5 years prior to clinical diagnosis with 91% sensitivity and 83% specificity. The aim of this study is to develop the tools necessary for further developing the assay into a diagnostic assay to be performed in our CLIA cap-certified lab and further down the road developing an IVD diagnostic kit. Validating this first-in-class methodology requires development of a controlled spike-in system that allows evaluation of the assay efficiency, accuracy, specificity and sensitivity to individual plasma matrix. We will determine the assay specified range, required volume and validate its linearity and precision between experiments/days. We will use mice model of AD to validate our hypothesis that NDE contents reflects that of brain neurons. We believe that these steps are needed to confidently advance to clinical validation of the test in a large retrospective clinical study, which is the goal of phase II of this grant. Attaining these aims will provide a robust test with established analytic and quality controls. Such an assay will put us in a strong position to engage co-development agreement with pharmaceutical companies to develop diagnostic and companion diagnostic assays that will contribute to the development of diseases modifying treatment for AD.
Public Health Relevance Statement: We are developing a unique blood test for Alzheimerâs disease (AD) preclinical detection, patient selection and treatment response monitoring. The test is based on immunoaffinity isolation of neuronal derived exosomes from plasma samples and measurement of their content as surrogates to brain neurons. Our blood test will have the potential to transform the way AD clinical trials are performed, from attempting to rescue severely injured neurons to earlier prevention, potentially improving the harsh 0.5% success rate of AD therapeutic development to the industry average of close to 5%.
Project Terms: Accreditation; Affect; Aging; Agreement; Alzheimer's Disease; Alzheimer's disease model; analytical tool; Antibodies; Baltimore; base; Biological Assay; Biological Markers; Blood; Blood Plasma Volume; Blood Tests; Brain; Brain Pathology; Caring; Cathepsins; Cell Line; Cells; Clinical; clinical Diagnosis; Clinical Research; Clinical Trials; clinically significant; commercial application; companion diagnostics; cost; Data; Dementia; Detection; Development; Diagnosis; Diagnostic; diagnostic assay; Disease; Disease Progression; disorder control; drug development; Early Diagnosis; early screening; Evaluation; exosome; experimental study; Failure; Frontotemporal Dementia; Goals; Grant; Hematological Disease; Hippocampus (Brain); hospital laboratories; Human; Immune; Impaired cognition; improved; Individual; Industry; injured; IRS1 gene; Label; Laboratories; Longitudinal Studies; Measurement; Measures; Membrane Proteins; Messenger RNA; Methodology; Modeling; Monitor; mouse model; Mus; Neural Cell Adhesion Molecule L1; Neuraxis; Neurologic; Neurons; non-demented; Outcomes Research; overexpression; Parents; Pathologic; Pathology; Patient Selection; Patients; Persons; Pharmacologic Substance; Phase; Plasma; Population; Positioning Attribute; pre-clinical; predictive test; Prevention; Procedures; programs; protein biomarkers; Proteins; Protocols documentation; prototype; Quality Control; Recovery; Research; research and development; Research Proposals; RNA; Running; Sampling; Sensitivity and Specificity; Serum; Small Business Innovation Research Grant; Specific qualifier value; Specificity; Stratification; success; Symptoms; Synapses; System; tau Proteins; Testing; Therapeutic; therapeutic development; Tissues; tool; Transgenic Mice; Transgenic Organisms; treatment response; Validation; Variant; Vesicle; Vi
