Kinetic Phenotype Discovery Informatics for Neurological Diseases

Project Summary Neurological disorders significantly outnumber diseases in other therapeutic areas and are growing in incidence faster than any other disease classesHoweverthe pharmaceutical industry has been unsuccessful in coming up with effective drugsA big factor in these failures has been a lack of adequate model systems for fundamental disease understanding affecting both diagnosis and treatmentThere is therefore a strongemerging interest in the use of patient derived cell models to understand the pathogenic mechanisms underlying neurological disease phenotypesTo gain a true understanding of these mechanisms and phenotypesit is necessary to analyze dynamic events using time lapse microscopyThese tools complement RNA profiling studies by enabling single cell resolution of pathogenic processes at high throughputenabling investigation of highly diverse or largely replicative patient sets at an unprecedented scaleTo discover predictive disease phenotypes across a large representative patient samplea systematicunbiased approach is needed to mine time lapse microscopy image sequencespatient clinical and concomitant dataThere is therefore a critical need for a next generation analytical tool to enable the discovery of disease predictive phenotypes robust to patient variationsThuswe propose to develop a teachable kinetic informatics discoveryKIDtool based on a hierarchical inference frameworkIf proventhe KID tool would be rapidly adopted for translational research using patient derived cell models in many diseasesIt could facilitate a paradigm shift towards broad adoption of patient cell models for therapeutics discoveryoptimizationstratification and diagnostic discoveryOur immediate objective for this Fast Track project is to develop and validate the KID tool by showing that it can classify patients on the basis of disease and disease characteristics such as age of onsetIn Phase I we will develop the prototype KID tool and preliminary patient panelWe will prove feasibility by discovering phenotypes and then accurately scoring patients based on the phenotypes in blind testsIn Phase II we will develop the full patient panel and pre product KID toolWe will validate by scoring patients in blind tests and validate phenotypes through corroboration with targeted transcriptional profiling and genomic testsWe will reduce the phenotypes to a single time point and show efficacy in a targeted compound screenThe Specific Aims arePhaseAimDevelop the prototype KID tool and preliminary patient panel incorporating neuronal firing reporterAimVerify the prototype KID tool in a preliminary patient panelPhase IIAimComplete the beta prototype KID tool and patient panel for KID tool validationAimDisease phenotype discovery and verification in the full patient panelAimDisease phenotype validation Project Narrative Neurological disorders significantly outnumber diseases in other therapeutic areas and are growing in incidence faster than any other disease classesHoweverthe pharmaceutical industry has been unsuccessful in coming up with effective drugsThere is interest in using patient derived cells as test beds for finding better ways to cure neurological diseasesHowever there are two critical challenges to overcome in order for patientderived cells to become a powerful new paradigm in health carethe in vitro differences between patients are large and it is difficult to know which differences are disease relevant and which are normal inter patient differencesandhow to come up with good methods to image cellular functions and infer from the imaging data the reliable metrics which can quantify the disease relevant differences and generate disease predictive metricsThis project proposes to take a quantum leap forward in translational disease research by combining patient specific cell modelsinnovative fluorescent probes and a next generation kinetic informatics discovery tool that will well equip scientists to efficiently discover the meaningful phenotypic differences between disease and healthy patients