Project Grant R44ES035556

A LIVER-ON-CHIP PLATFORM TO EVALUATE PANELS OF CLINICALLY RELEVANT GENE VARIANTS FOR SCREENING OF XENOBIOTIC COMPOUNDS - PROJECT SUMMARY GENETIC PREDISPOSITIONS IN THE HUMAN POPULATION ARE ASSOCIATED WITH UNPREDICTABLE PHARMACOKINETIC (PK) AND PHARMACODYNAMICS (PD), WHICH RESULT IN THE LOSS OF TREATMENT EFFICACY OR INCREASE RISKS OF ADVERSE DRUG REACTIONS (ADRS). THE FDA ESTIMATES THAT ADRS ARE THE 4TH LEADING CAUSE OF DEATH IN THE US, AND TREATMENT COSTS RELATED TO ADRS EXCEED $136 BILLION ANNUALLY. DRUG-INDUCED LIVER INJURY LEADS TO INCREASED MORBIDITY AND MORTALITY IN PATIENTS AND REMAINS A MAJOR REASON FOR DRUG ATTRITION IN THE MARKET. SINCE THERE ARE INTERSPECIES DIFFERENCES IN RESPONSE TO XENOBIOTICS, NEW METHODS MUST BE DEVELOPED TO CAPTURE HUMAN GENETIC VARIABILITY IN RESPONSE TO CHEMICAL EXPOSURES AND TO HELP PROTECT SENSITIVE POPULATIONS THAT RESPOND DIFFERENTLY TO DRUG EXPOSURES. THIS SBIR FAST-TRACK IS FOCUSED ON GENERATING A LIVER-ON-CHIP PLATFORM TO EVALUATE PANELS OF CLINICALLY RELEVANT GENE VARIANTS FOR SCREENING OF XENOBIOTIC COMPOUNDS. ONCE SUCCESSFULLY DEVELOPED, VALIDATED, AND COMMERCIALIZED, THE LIVER-ON-CHIP PLATFORM WILL SERVE AS AN IMPORTANT NEW TOOL IN CHEMICAL TOXICITY SCREENING, PROVIDING A MORE PREDICTIVE IN VITRO TOOL FOR ASSESSING HEPATOTOXICITY DURING THE PRECLINICAL STAGE THAT WILL PREVENT UNSAFE DRUG CANDIDATES FROM ADVANCING INTO CLINICAL TRIALS. THE APPROACH PROPOSED IN THIS APPLICATION LEVERAGES AN EXISTING, WELL CHARACTERIZED LIVER-ON-CHIP MODEL, THE LIVER ACINUS MICROPHYSIOLOGY SYSTEM (LAMPS). LAMPS IS A 3D LAYERED TISSUE MODEL GENERATED THROUGH SEQUENTIAL CELL LAYERING AND SUBSEQUENT TISSUE SELF-ORGANIZATION. THE ENVISIONED ADVANCED LAMPS INCLUDES A PANEL OF HEPATOCYTES WITH GENETIC VARIATIONS THAT ARE KNOWN TO HAVE CLINICAL SIGNIFICANCE AND THAT CAN BE COMPARED REGARDING THEIR TOXICITY RESPONSE TO XENOBIOTICS. ASSAY OUTPUTS ARE INTEGRATED INTO THE BIOSYSTICS ANALYTICS PLATFORMTM TO CORRELATE AND ANALYZE IN VITRO RESULTS TO CLINICAL DATA AND COMPUTATIONALLY MODEL THE LAMPS DATA IN A SINGLE WEB-BASED PLATFORM. PHASE I IS DESIGNED TO ESTABLISH THE FEASIBILITY OF LAMPS TO MODEL HUMAN VARIABILITY FOR LIVER TOXICOLOGY STUDIES. WE WILL LEVERAGE THE NORTIS' SECOND-GENERATION PARVIVOTM ORGAN-ON-CHIP PLATFORM THAT SUPPORTS 768 SIMULTANEOUS HIGH-CONTENT ASSAYS PER STANDARD CELL INCUBATOR, AS WELL AS PREVIOUSLY ESTABLISHED LAMPS CULTURE PROTOCOLS. PHASE I/AIM 1 IS DESIGNED TO ESTABLISH EVIDENCE THAT LAMPS GENERATED FROM PRIMARY LIVER CELLS WITH GENETICALLY DIVERSE POLYMORPHISMS SHOW CLINICALLY RELEVANT DIFFERENCES IN RESPONSE TO EXPOSURE TO REFERENCE DRUGS. PHASE II WILL DEVELOP THE CORE PANEL OF A GENETICALLY DIVERSIFIED LIVER TOXICOLOGY SCREENING PLATFORM. PHASE II/AIM 1 WILL DETERMINE THE SOURCE OF CELLS FOR THE FUTURE HUMAN LIVER TOXICITY SCREENING PLATFORM. IN PHASE II/AIM 2 WE WILL DEVELOP THE CORE PANEL OF LAMPS WITH GENETIC POLYMORPHISMS AND VALIDATE THE PANEL THROUGH CORRELATION WITH CLINICAL DATA. ONCE COMMERCIALIZED, THE ENVISIONED PLATFORM WILL GIVE RESEARCHERS THE OPPORTUNITY TO TEST DRUG CANDIDATES AND OTHER XENOBIOTICS IN HUMAN LIVER MODELS REPRESENTING SUB-POPULATIONS OF INDIVIDUALS WHO POSSESS A SPECIFIC GENE VARIANT.