SBIR-STTR Award

Drug developers desperately need better tools in the laboratory to improve the 90% failure rate of drugs in clinical trials. Liver toxicity is still the leading cause of drug failure, despite extensive preclinical testing in surrogate animal species. HemoShear develops human surrogate technologies for target ID and validation and screening of compounds for safety and efficacy in the late discovery and early pre-clinical stages. HemoShear has developed a human vascular surrogate technology for identification and validation of novel targets and for screening and selection of optimal compounds for further development (US Patent 60/879,710 under review). Our human vascular surrogate device uniquely mimics the vascular anatomy (co- culture containing endothelial and smooth muscle cells, separated by a porous membrane) and hemodynamic environment during the early stages of atherosclerosis. The device enables investigation of the cellular and molecular mechanisms of human atherosclerosis and the identification of novel biomarkers and transcriptional pathways for development of improved drug therapies. Cell-based surrogate models are being used increasingly during drug development to provide more accurate predictions of human responses. This Phase I SBIR application proposes to develop a hemodynamic co-culture model of the liver using HemoShear's proprietary platform technology that will represent a far superior system with which to screen drug potential for hepatotoxicity, determine mechanisms of liver toxicity and identify novel targets for therapy. It is widely known that static, monoculture hepatocyte models utilized to study drug efficacy and toxicity are not predictive of the in vivo response, and represent ineffective models for target identification and validation in the drug development process because of the inherent loss of differentiated phenotype. Like the vasculature, recreating anatomical and physiological features important to normal liver function is necessary for an effective ex vivo model. For example, the biological response of the liver in vivo to both endogenous substrates as well as exogenous factors is dependent on the direct and indirect 'cross-talk' between the different cell types of the endothelium and epithelium. In addition, their survival and gene expression profiles are largely dependent on the local hemodynamics. Thus, the overall goal of this proposal is to develop a rat liver co-culture surrogate model that mimics in vivo physiology and hemodynamics. The model will consist of sinusoidal endothelial cells (SECs) and hepatocytes in co-culture where the SECs are exposed to sinusoid fluid hemodynamics, recreating in vivo cell phenotypes, ex vivo. If successful, this system will allow pharmaceutical companies to better understand the specific mechanism-of-action for drug efficacy and pre-clinical safety/toxicity compared to current monoculture, static systems. Additionally, success of this Phase I SBIR will lead to a Phase II application to develop a more advanced human model of hepatotoxicity and inflammatory disease, incorporating additional cell types, e.g. Kupffer and stellate cells.

Public Health Relevance:
Drug developers desperately need better tools in the laboratory to improve the 90% failure rate of drugs in clinical trials. Liver toxicity is still the leading cause of drug failure, despite extensive preclinical testing in surrogate animal species. HemoShear develops human surrogate technologies for target ID and validation and screening of compounds for safety and efficacy in the late discovery and early pre-clinical stages. This Phase I SBIR application proposes to develop a hemodynamic rat sinusoidal endothelial cell and hepatocyte co-culture model of the liver using HemoShear's proprietary platform technology;which will represent a far superior system to screen drug potential for hepatotoxicity, determine mechanisms of liver toxicity and identify novel targets for therapy. Success of this Phase I SBIR will lead to a Phase II application to develop a more advanced human model of hepatotoxicity and inflammatory disease, incorporating additional cell types, e.g. Kupffer and stellate cells.

Thesaurus Terms:
2,4,6(1h,3h,5h)-Pyrimidinetrione, 5-Ethyl-5-Phenyl-;Apap;Acetamide, N-(4-Hydroxyphenyl)-;Acetamidophenol;Acetaminophen;Acetominophen;Address;Albumins;Anatomic;Anatomical Sciences;Anatomy;Animals;Assay;Atheroscleroses;Atherosclerosis;Atherosclerotic Cardiovascular Disease;Bioassay;Biologic Assays;Biological;Biological Assay;Biological Models;Blood Vessels;Blood Flow;Body Tissues;Co2;Carbon Dioxide;Carbonic Anhydride;Cell Differentiation;Cell Differentiation Process;Cell Line;Cell Lines, Strains;Cellline;Cells;Clinical Trials;Clinical Trials, Unspecified;Clofibrate;Clofibric Acid, Ethyl Ester;Co-Culture;Cocultivation;Coculture;Coculture Techniques;Common Rat Strains;Cytokines, Chemotactic;Data;Detection;Development;Devices;Discontinuous Capillary;Disease;Disorder;Drug Evaluation, Preclinical;Drug Screening;Drug Therapy;Drug Toxicity;Drugs;Electrons;Endothelial Cells;Endothelium;Environment;Enzymes;Epithelium;Ethyl Chlorophenoxyisobutyrate;Evaluation;Evaluation Studies, Drug, Pre-Clinical;Evaluation Studies, Drug, Preclinical;Exogenous Factors;Exposure To;Expression Profiling;Expression Signature;Flr;Failure (Biologic Function);Figs;Figs - Dietary;Gene Expression;Genes;Goals;Hepatic Cells;Hepatic Parenchymal Cell;Hepatocyte;Hepatotoxic Effect;Hepatotoxicity;Homologous Chemotactic Cytokines;Human;Human, General;Hydroxyacetanilide;Inflm;Immunofluorescence;Immunofluorescence Immunologic;Immunologic, Immunofluorescence;Incubators;Inflammation;Inflammatory;Intercrines;Intermediary Metabolism;Investigation;Kupffer Cells;Kupffer's Cell;Laboratories;Lead;Legal Patent;Leiomyocyte;Liquid Substance;Liver;Liver Cells;Liver Toxicity;Metbl;Mammals, Rats;Mammals, Rodents;Man (Taxonomy);Man, Modern;Medication;Membrane;Metabolic;Metabolic Processes;Metabolism;Microscopic;Model System;Modeling;Models, Biologic;Molecular;Molecular Fingerprinting;Molecular Profiling;Myocytes, Smooth Muscle;N-(4-Hydroxyphenyl)Acetanilide;N-Acetyl-P-Aminophenol;Negative Beta Particle;Negatrons;Paracetamol;Patents;Pathway Interactions;Pattern;Pb Element;Pharmaceutic Preparations;Pharmaceutical Agent;Pharmaceutical Preparations;Pharmaceuticals;Pharmacologic Substance;Pharmacological Substance;Pharmacotherapy;Phase;Phenemal;Phenobarbital;Phenobarbitone;Phenotype;Phenylbarbital;Phenylethylbarbituric Acid;Physiologic;Physiological;Physiology;Preclinical Drug Evaluation;Preclinical Testing;Procedures;Process;Propanoic Acid, 2-(4-Chlorophenoxy)-2-Methyl-, Ethyl Ester;Rt-Pcr;Rtpcr;Rat;Rattus;Relative;Relative (Related Person);Reverse Transcriptase Polymerase Chain Reaction;Rodent;Rodentia;Rodentias;Sbir;Sbirs (R43/44);Sis Cytokines;Safety;Sampling;Science Of Anatomy;Screening Procedure;Side;Sinusoid;Sinusoidal Capillary;Small Business Innovation Research;Small Business Innovation Research Grant;Smooth Muscle Cells;Smooth Muscle Myocytes;Smooth Muscle Tissue Cell;Staging;Stellate Sinusoidal Macrophage;System;System, Loinc Axis 4;Technology;Time;Tissues;Toxic Effect;Toxic Effect On Liver Cells;Toxicities;Validation;Xenobiotic Metabolism;Anatomy;Atheromatosis;Atherosclerotic Vascular Disease;Base;Biomarker;Body System, Hepatic;Cell Type;Chemoattractant Cytokine;Chemokine;Clinical Investigation;Cultured Cell Line;Cytokine;Cytotoxicity Test;Disease /Disorder;Disease/Disorder;Drug /Agent;Drug Development;Drug Discovery;Drug Efficacy;Drug/Agent;Failure;Fluid;Heavy Metal Pb;Heavy Metal Lead;Hemodynamics;Hepatoxicity;Improved;In Vivo;Liquid;Liver Function;Liver Macrophage;Membrane Structure;Model;Molecuar Profile;Molecular Signature;Novel;Organ System, Hepatic;P-Acetamidophenol;P-Hydroxyacetanilide;Pathway;Polycarbonate;Pre-Clinical;Preclinical;Preconditioning;Response;Reverse Transcriptase Pcr;Screening;Screenings;Stellate Cell;Success;Tool;Vascular

There is a critical need to improve the accuracy of preclinical drug efficacy and toxicity screening and testing through the development of human hepatocyte (liver) in vitro culture systems that more effectively mimic the human in vivo environment. HemoShear is a biotechnology research company that utilizes patented methodologies to restore in vivo responsiveness to human primary cells in vitro. Under Phase I SBIR R43DK091104, we developed a predictive rat primary hepatocyte system that restores morphology, function, transport, metabolism and respond to drugs and growth factors at nearer to in vivo levels. The principles to develop the rat system, translated to human primary hepatocytes, restoring morphology, function, metabolism and drug response at in vivo drug levels achieved in humans. To our knowledge, there are no commercially available systems that can achieve this level of hepatobiology and in vivo responsiveness in human primary hepatocytes ex vivo. The purpose of Phase II SBIR R44DK091104 is to further develop and validate a predictive primary human hepatocyte system for use in investigative toxicology, safety assessment and drug discovery with our commercial partners. Our Aims will achieve this using an integrated experimental, genomic and computational approach, screening more than 40 compounds in the system.

Public Health Relevance Statement:


Public Health Relevance:
There is a critical need to improve the accuracy of preclinical drug efficacy and toxicity screening and testing through the development of human hepatocyte (liver) in vitro culture systems that more effectively mimic the human in vivo response. HemoShear is a biotechnology research company that utilizes patented methodologies to restore in vivo responsiveness to human primary cells in vitro. The purpose of Phase II SBIR R44DK091104 is to further develop and validate a predictive primary human hepatocyte system for use in investigative toxicology, safety assessment and drug discovery with our commercial partners by screening more than 40 drugs in the system.

Project Terms:
Active Biological Transport; Albumins; Bile fluid; Biological; Biotechnology; Blood Vessels; body system; Cardiovascular system; Cells; Clinical; Clinical Trials; Collagen; Combined Modality Therapy; commercialization; Computer Simulation; CYP1A1 gene; Cytochrome P450; cytotoxicity; Data Set; Databases; Development; Dose; drug candidate; Drug Compounding; drug development; drug discovery; drug efficacy; drug metabolism; Drug toxicity; End Point Assay; Environment; Exhibits; Gel; Genes; genome-wide; Genomics; Gold; Growth Factor; hemodynamics; Hepatocyte; Human; Human Development; Image; improved; In Vitro; in vivo; Legal patent; Letters; Liver; Machine Learning; Metabolism; Methodology; Methods; Morphology; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology and Toxicology; Phase; Phenobarbital; Physiological; pre-clinical; Preclinical Drug Evaluation; Predictive Value; Production; Property; Protein Analysis; Protein Isoforms; public health relevance; Qualifying; Randomized; Rattus; Relative Risks; Research; response; Rifampin; RNA; Running; Safety; screening; Small Business Innovation Research Grant; System; Technology; Testing; Toxic effect; Toxicology; transcriptomics; Translating; Urea; Validation; Vascular System