Phase II year
2015
(last award dollars: 2016)
Phase II Amount
$1,689,857
Human inducible pluripotent stem cells (iPSCs) proliferate readily and can be terminally differentiated into hepatocytes, which potentially makes them an attractive, cost-effective resource compared to primary human hepatocytes. Moreover, the ability to standardize a platform to a single human donor, or donor(s) who may include known genetic drug metabolism polymorphism(s), can eliminate or greatly reduce donor-donor variability associated with primary hepatocytes. Unfortunately, it has been clearly demonstrated that differentiated iPSC-derived hepatocytes (iHCs), though similar to primary hepatocytes in many ways, retain certain "fetal"-like aspects. This includes increased expression of fetal-like proteins, e.g.??fetal protein, and decreased activity of specific cytochrome p450 enzymes, e.g. the CYP3A family, which is responsible for metabolizing over 60% of drugs. Thus, the pharmaceutical industry and regulatory agencies view the use of iHCs as promising but currently limited. Attempts to "mature" these cells in novel hepatocyte platforms have not proven successful. HemoShear is a biotechnology research company that utilizes patented methodologies to restore in vivo responsiveness to human primary cells in vitro. We commercialized a human primary hepatocyte platform that combines physiological principles of controlled hemodynamics and transport to restore and maintain mature, in vivo-like differentiated phenotype, morphology and metabolic function. Hepatocytes in this platform respond to drugs and hormones at in vivo concentrations. The purpose of this Fast-Track SBIR is to develop an iHC platform using the HemoShear technology to mature iHC differentiated function and drug responses at physiological levels, providing the framework for commercializing a much needed platform for drug safety and efficacy assessment.
Public Health Relevance Statement: Public Health Relevance: Human inducible pluripotent stem cells (iPSCs) proliferate readily and can be terminally differentiated into hepatocytes, which potentially makes them an attractive, cost-effective resource compared to primary human hepatocytes for drug discovery and development. Unfortunately, it has been clearly demonstrated that differentiated iPSC-derived hepatocytes (iHCs), though similar to primary hepatocytes in many ways, retain certain "fetal"-like aspects. Thus, the pharmaceutical industry and regulatory agencies view the use of iHCs as promising but currently limited. HemoShear is a biotechnology research company that utilizes patented methodologies to restore in vivo responsiveness to human primary cells in vitro. The purpose of this Fast- Track SBIR is to develop an iHC platform using the HemoShear technology to mature iHC differentiated function and drug responses at physiological levels, providing the framework for commercializing a much needed platform for drug safety and efficacy assessment.
NIH Spending Category: Biotechnology; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Induced Pluripotent Stem Cell; Stem Cell Research - Induced Pluripotent Stem Cell - Human
Project Terms: Albumins; Benchmarking; Biological; Biological Products; Biological Transport; Biotechnology; Blood Circulation; Cell Culture Techniques; Cell Survival; Cells; Clinical; cost effective; Culture Media; CYP2D6 gene; CYP3A4 gene; Cytochrome P450; cytotoxicity; Development; Differentiation Antigens; drug candidate; drug development; drug discovery; Drug Formulations; Drug Industry; drug metabolism; End Point Assay; Enzymes; Family; fetal; Fetal Proteins; Gene Expression; gene panel; Genetic; Genetic Polymorphism; Health; hemodynamics; Hepatocyte; Hormones; Human; Image; In Vitro; in vivo; induced pluripotent stem cell; Industry; International; Legal patent; Letters; Literature; Liver; Measurement; Measures; Metabolic; Methodology; Methods; Morphology; novel; Omeprazole; Performance; Pharmaceutical Preparations; Phase; Phenobarbital; Phenotype; Physiological; Plasma; Pluripotent Stem Cells; Proliferating; Property; Protein Analysis; Proteins; Publishing; Qualifying; Relative (related person); Research; Resources; response; Risk; RNA; Running; Safety; Small Business Innovation Research Grant; success; System; Technology; Therapeutic; Toxic effect; Urea
