Development of a Human Liver Microphysiological System For Alcoholic Liver Disease

PROJECT SUMMARYAlcoholic liver diseaseALDincludes a broad range of progressive disease stagesfatty liveralcoholic steatohepatitisASHliver fibrosisliver cirrhosisand hepatocellular carcinomaIn spite of being one of the major causes of morbidity and mortality in the worldthere are currently no effective strategies that can preventtreat or monitor the progress of ALD owing primarily to lack of human and physiologically relevant research modelsAt Emulate we have developed proprietary technology to build human microphysiological systems recapitulating tissue architecture to achieve organ level physiological functionsWe have recently used this technology and developed a maturefunctional human Liver Chip we can maintain for more than four weeks in cultureOur proposed research will focus on developing the ALD Chip based on the current model of Liver ChipThe goal of the proposed Phase I SBIR is to develop a humanphysiologically relevant ALD model on chip and recapitulate the different stages of human disease progression from potential for reversibility as it has been well described in human patientsto the different stages of the irreversible diseaseAlong these lines we will develop the ALD Chip to model the main aspects of ALDincluding alcoholic fatty liver and alcoholic hepatitis steatosisASHPhase Iand eventuallyPhase IIthe alcoholic fibrotic disease stageEmulateandapos s developed Liver Chip is a microphysiological system constructed with primary human hepatic cellsthe gold standard in the fieldinside a microengineered environment incorporating flowthat emulates the liver sinusoid space architecture and allows for dynamic assessment of liver functions over timeBased on this recent development that provides significant improvements as compared to the previously described in vitro systems for human liver studieswe are now enabled to apply ethanol concentrations relevant to those measured in human patients blood and monitor development of human ALD on the Chip using clinically relevant endpointsCombination of ethanol dosing and length of experimentation should recapitulate the different stages in ALD progression including capability for reversibility of the established phenotypeThe proposed research for Phase I of this SBIR has two aimsiThe development and optimization of human ALD Chip by characterizing the dose response to physiological relevant ethanol dosing conditionsAim Iandiito validate the in vivo relevance of human ALD Chip developed in Aimby the characterization of the progression of different ASH stages in the ALD Chipalcoholic fatty liver andalcoholic hepatitis and determine the reversibility of the pathology in association to severity and time as in the human diseaseWe plan to optimize the ALD Chip to provide the scientific community with a platform for new drug development and screening for liver injury therapiestreatments for protection of alcohol users from transitioning to more severe disease stages associated with a number of co morbiditiesFurtheras all Emulateandapos s Organ Chips are based on human primary cells they can be used to provide insights on patient specific responsesas neededand to support targeted diagnostic and prognostic biomarkers discoveryIn conclusionwe propose to develop an ALD Chip to translate ALD preclinical data into a testable and clinically relevant ALD model enabling a better understanding of this disease and support of drug discovery PROJECT NARRATIVE Alcoholic liver diseaseALDas developed gradually following moderate to heavy drinkingis associated with a number of other serious diseases and increased mortalityThe available research models for studying this disease have not been successful in recreating major characteristics of the progress of this disease in humans and as a result to provide insights for neweffective drug developmentsDespite the profound economic and health impactthere is no Food and Drug Administration approved therapy for any stage of ALDemphasizing the need for research to identify new specificefficient treatments for the different stages of ALD in human patientsIn this proposal we aim to combine recent advances in engineeringbiology and medicine to develop a human ALD Chip to address the above unmet needs in human ALDAt Emulate we have proprietary technology on the organs on chips we apply to develop human organ chips that can faithfully recapitulate the architecture and functionality of human organsAlong these lines we have recently developed a human LiverChip that provides the best available dynamic human liver model as it concerns organ level functions over a prolongedfour weeks periodwe will use for the modelling of the different ALD stagesalcoholic fatty liverASH and alcoholic fibrosisWe will focus particularly in the mechanisms and endpoints associated with the potential for reversibility of the pathologyas described in human patientsThis project will generate the proof of concept that the Emulateandapos s ALD chip can be optimized to provide a humanclinically relevant platform for studying ALD in humans and support new drug discovery and biomarkers identification in a patient specific manner