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.
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.
| Chapman, Kimberly A; Collado, Maria S; Figler, Robert A et al. (2016) Recapitulation of metabolic defects in a model of propionic acidemia using patient-derived primary hepatocytes. Mol Genet Metab 117:355-362 |
