Drug induced liver injury (DILI) is a concern for patients, clinicians, the FDA, and the pharmaceutical industry as the leading cause of clinical drug attrition and post-marketing drug withdrawals. According to the FDA, DILI has been the most frequent cause of safety-related drug withdrawals for the past 50 years. As a potential solution to the problem, the IQ-MPS Affiliate to the International Consortium for Innovation and Quality in Pharmaceutical Development highlighted the need to qualify human liver microphysiological systems (MPS) for DILI context of use (CoU) with a set of pragmatic engineering and quality requirements for the MPS implementation into standard operating procedures. During an ongoing NCATS SBIR, Lena Biosciences (LB) developed and commercialized an SLAS-standardized, Perfused Organ Panel MPS that meets these prerequisites. The ultimate goal of this SBIR is to qualify the MPS with a revolutionary synthetic hemoglobin, Blood Substitute, for DILI CoU using the guidance of the FDA CDER and the IQ-MPS Affiliate. Our recent publication (Front. Mol. Biosci. 2020) shows that the MPS restores cellular oxidative metabolism in diverse, perfused, 3D liver models, significantly increasing cell respiration by mitochondrial electron transport chain, CYP450 oxidation required for metabolism of drugs, and OXPHOS ATP production required for holistic cell function, and all cell processes from active transport of molecules across the cell membrane to organelle function. An OXPHOS-competent model of cellular redox homeostasis will provide in vivo-like cell sensitivity to drugs and their reactive metabolites and free radicals, and drug-induced oxidative and nitrosative stress that leads to the loss of cellular antioxidant defense for comprehensive characterization of DILI threats, positioning the MPS to adequately meet biological qualification prerequisites for DILI CoU. While numerous factors contributing to DILI have been reported, to date there is no consensus on the rank of these factors for in vitro testing using primary human cells, and on the types of in vitro assays that are the most relevant for DILI prevention. Therefore, in this SBIR we will focus on testing those compounds that the drug industry found the most difficult to de-risk, examine the role of oxidative cell stress in the sequence of cellular events that lead to DILI, provide mechanism-informative insight into the DILI sequelae using a battery of assays to isolate the trigger(s) and identify causalities, and resolve temporal and log-fold change in biomarkers, including the FDA-designated biomarkers for clinical exploration, relative to vehicle controls and in relation with the coinciding rise of ALT and ALP, clinical DILI biomarkers, in order to isolate those with the highest log-fold change and specificity at low or moderate ALT. To successfully carry out the studies and ensure the project's success, we have assembled a team of experts in advanced, OXPHOS-competent cell cultures (LB), and predictive screening of drug-induced livery injury (Dr. Salman Khetani, UIC).
Public Health Relevance Statement: Drug-induced liver injury is a significant problem for patients and clinicians, accounting for 5% of all hospital admissions, 50% of all cases of acute liver failure with approximately 30% of patients with acute liver failure requiring a liver transplant. This project will lay out foundation for sensitive, reliable, and predictive testing of potential drug liabilities using advanced models of human adverse response to reduce the risk and the incidence of unexpected liver injury, and provide a systematic testing methodology that leads to better understanding of causal associations for clinical decision making.
Project Terms: NAPQI; cytokine; Mediating; injury prevention; drug withdrawal; Acute Liver Failure; Acute Hepatic Failure; Fulminant Liver Failure; Fulminating Hepatic Failure; Fulminating Liver Failure; fulminant hepatic failure; Reactive Oxygen Species; Active Oxygen; Oxygen Radicals; Pro-Oxidants; Injury; injuries; base; Organ; Pump; Procedures; Clinical; Phase; Biological; biologic; Ensure; Hepatic Cells; Hepatic Parenchymal Cell; Liver Cells; Hepatocyte; peripheral blood; insight; Hepatotoxic effect; Liver Toxicity; Toxic effect on liver cells; hepatic toxicity; hepatoxicity; Hepatotoxicity; Cell Membrane Proteins; drug use; Drug usage; Oxidative Stress; analog; Cellular Respiration; aerobic metabolism; aerobic respiration; oxidative metabolism; Cell Respiration; Fe element; Iron; Consensus; Immunes; Immune; Complex; Event; 3-D; 3D; three dimensional; 3-Dimensional; Lytotoxicity; cytotoxicity; membrane structure; Membrane; success; Cellular injury; cell damage; cellular damage; damage to cells; injury to cells; cell injury; Toxicities; Toxic effect; drug metabolism; Prevention; Reporting; Position; Positioning Attribute; Modeling; response; liver ischemia; hepatic ischemia; T-Cell Activation; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; Pharmacologic Substance; Causality; causation; disease causation; Etiology; International; in vitro Assay; in vivo; Cellular Stress; cell stress; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Development; developmental; Pathway interactions; pathway; Heme Group; innovation; innovate; innovative; Cell model; Cellular model; drug testing; drug detection; Biological Markers; bio-markers; biologic marker; biomarker; nitrosative stress; in vitro testing; clinical decision-making; adaptive immunity; liver injury; Injury to Liver; hepatic damage; hepatic injury; liver damage; HepG2; Hep G2; HepG2 cell line; extracellular vesicles; Drug Screening; human model; model of human; predictive test; predictive assay; microphysiology system; microphysiologic model; microphysiologic platform; microphysiologic system; microphysiology model; microphysiology platform; adverse drug reaction; National Center for Advancing Translational Sciences; NCATS; drug induced liver injury; drug induced hepatotoxicity; drug induced liver disease; Accounting; Acetaminophen; APAP; Acetamidophenol; Acetominophen; Hydroxyacetanilide; Paracetamol; Affect; Animals; inhibitor; Antioxidants; anti-oxidant; Bile Acids; Bile Acids and Salts; bile salts; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Sciences; Biologic Sciences; Bioscience; Life Sciences; Active Biological Transport; Active Biologic Transport; Active Transport; Uphill Transport; Biotechnology; Biotech; Blood; Blood Reticuloendothelial System; Blood Substitutes; Artificial Blood; Artificial Erythrocytes; Erythrocyte Substitutes; Red Cell Substitutes; Cell Culture Techniques; cell culture; cell cultures; Cell Death; necrocytosis; cell growth; Cellular Expansion; Cellular Growth; Cell membrane; Cytoplasmic Membrane; Plasma Membrane; plasmalemma; Cell physiology; Cell Function; Cell Process; Cellular Function; Cellular Physiology; Cellular Process; Subcellular Process; Cells; Cell Body; Cholestasis; Bile Duct Obstruction; Biliary Stasis; bile obstruction; bile occlusion; cholestatic diseases; cholestatic disorder; cholestatic liver disease; cholestatic liver disorder; cholestatic syndromes; Drug Industry; Pharmaceutic Industry; Pharmaceutical Industry; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Electron Transport; electron transfer; Energy-Generating Resources; energy source; Engineering; Enzymes; Enzyme Gene; Erythrocytes; Blood erythrocyte; Erythrocytic; Marrow erythrocyte; Red Blood Cells; Red Cell; blood corpuscles; Foundations; Free Radicals; Galactose; D-Galactose; Galactopyranose; Galactopyranoside; Glucose; D-Glucose; Dextrose; Glutathione; gamma-L-Glu-L-Cys-Gly; gamma-L-Glutamyl-L-Cysteinylglycine; glutathione peroxidase; Goals; Hemochromatosis; Bronze Diabetes; iron storage disorder; Hemoglobin; Homeostasis; Autoregulation; Physiological Homeostasis; Hospitalization; Hospital Admission; Human; Modern Man; In Vitro; Incidence; Industry; Lead; Pb element; heavy metal Pb; heavy metal lead; Lipid Peroxidation; Liver; hepatic body system; hepatic organ system; liver transplantation; Hepatic Transplantation; Liver Grafting; Liver Transplant; Marketing; Membrane Lipids; Cell Membrane Lipids; Methodology; Mitochondria; mitochondrial; Organelles; oxidation; Redox; oxidation reduction reaction; Oxidation-Reduction; Oxidative Phosphorylation Pathway; Oxidative Phosphorylation; O element; O2 element; Oxygen; Parents; Patients; Perfusion; Production; Scientific Publication; Publications; Ischemia-Reperfusion Injury; Reperfusion Damage; Reperfusion Injury; respiratory mechanism; Respiration; Risk; social role; Role; Running; Safety; Specificity; Standardization; Stress; T-Cells; thymus derived lymphocyte; T-Lymphocyte; Testing; Tissues; Body Tissues; Triage; heme a; N-acetyl-4-benzoquinoneimine; N-acetyl-4-benzoquinone imine; N-acetyl-p-benzoquinoneimine; NABQ
