Nonalcoholic fatty liver disease (NAFLD) is a chronic condition that originates as lipid accumulation within hepatocytes (steatosis) and progresses into nonalcoholic steatohepatitis (NASH), characterized by lipid accumulation, inflammation, oxidative stress, and fibrosis. An estimated 100 million adults across the U.S. are thought to have NAFLD, with up to 20 million more estimated to have NASH. Left unchecked, the disease can advance to cirrhosis and hepatocellular carcinoma. Currently, NASH contributes to one third of hepatocellular carcinomas in the US and is the second leading cause of liver transplants in the US. NASH is often referred to as a silent disease as most patients are asymptomatic until problems arise from cirrhosis and liver failure and diagnosis only possible via invasive liver biopsies. Despite well-defined morphological features and decades of intense research worldwide, the mechanisms of NAFLD progression as well as therapeutic approaches and non-invasive diagnostics are still resoundingly absent. Recently, Organovo developed ExVive Human Liver Tissue, an in vitro 3D bioprinted liver model comprising primary human hepatocytes, hepatic stellates and endothelial cells that better mimics native human liver biology over extended time in culture. The technological advancement of 3D bioprinting enables controlled, reproducible fabrication of 3D liver tissues ex vivo from human cells, yielding a durable liver model with complex composition and architecture that retains metabolic competence and liver-specific functions for at least 4 weeks in culture. The current Fast Track SBIR application seeks to utilize ExVive Human Liver Tissue to model the onset and progression of human NAFLD via nutrient overload in the first Phase, followed by induction of inflammation, oxidative stress and fibrosis to mimic human NASH in the second Phase. Importantly, in order to drive adoption, the steatosis and NASH models will be validated via comparisons of genomic data with clinically confirmed NAFLD patient data in collaboration with key opinion leader Dr. David Brenner, and verification of altered drug metabolism and disposition via CYP1A2 and 2C9 activities. Lastly, prevention of NAFLD progression and regression of NASH will be assessed via therapeutic modulation of disease phenotypes. Together, these in vitro models have the potential to significantly impact liver disease research by enabling the discovery of novel therapeutics, biomarkers to non-invasively delineate NASH from steatosis, and allow the safety assessment of drugs in a disease relevant background.
Public Health Relevance Statement: PROJECT NARRATIVE Nonalcoholic fatty liver disease (NAFLD) is a chronic condition that originates as lipid accumulation within hepatocytes (steatosis) and progresses into nonalcoholic steatohepatitis (NASH), characterized by lipid accumulation, inflammation, oxidative stress, and fibrosis. Despite decades of intense research worldwide, the mechanisms of NAFLD progression as well as therapeutic approaches and non-invasive diagnostics for NASH are still lacking. The current Fast Track SBIR application seeks to utilize Organovos ExVive Human Liver Tissue to model steatosis (Phase I) and its progression to NASH (Phase II) in vitro, with verification of the clinical relevance of the models against patient data and modulation of disease phenotype by therapeutic intervention. If successful, this model will provide an unprecedented tool for the advancement of NAFLD basic research, biomarker identification and drug development, significantly impacting patient lives.
Project Terms: Adoption; Adult; Agonist; Architecture; Basic Science; Biochemical; Biological Assay; Biological Markers; Biological Models; Biology; biomarker identification; bioprinting; California; Cell Culture Techniques; cell type; Cells; Chemicals; Chronic; Chronic Disease; Cirrhosis; Clinical; clinical phenotype; Clinical Trials; clinically relevant; Collaborations; Comorbidity; Competence; Complex; Confidential Information; CYP1A2 gene; CYP2C9 gene; cytokine; Data; Development; Diagnosis; Disease; disease diagnosis; disease phenotype; Disease Progression; Disease regression; drug development; drug metabolism; Dyslipidemias; Endothelial Cells; Enhancers; Enzymes; Fatty Acids; Fatty Liver; fibrogenesis; Fibrosis; Gene Expression; genipin; genomic data; Glucose; Health; Hepatic; Hepatic Stellate Cell; Hepatocyte; Histologic; Histology; Human; human disease; Hypertension; Immunocompetence; improved; In Vitro; in vitro Model; Inflammation; Inflammatory; inhibitor/antagonist; Interleukin-1 beta; Kupffer Cells; Left; Lipids; Lipopolysaccharides; Literature; Liver; liver biopsy; Liver diseases; Liver Failure; liver transplantation; macrophage; MAP3K5 gene; Measures; Mediating; Metabolic; Modeling; Molecular; Morphology; non-alcoholic fatty liver; nonalcoholic steatohepatitis; Nonesterified Fatty Acids; noninvasive diagnosis; novel; novel therapeutics; Nutrient; Obesity; Oleic Acids; Oxidative Stress; Palmitic Acids; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phase; Phenotype; Pioglitazone; Prevention; Primary carcinoma of the liver cells; profiles in patients; Reproducibility; Research; Rodent Model; Safety; screening; Small Business Innovation Research Grant; specific biomarkers; standard of care; System; Therapeutic; Therapeutic Intervention; Time; Tissue Model; Tissues; tool; transcriptome sequencing; Universities; uptake; Validation
