Translation of Human-Induced Pluripotent Stem Cells: From Clinical Trial in a Dish to Precision Medicine

Abstract

The prospect of changing the plasticity of terminally differentiated cells toward pluripotency has completely altered the outlook for biomedical research. Human-induced pluripotent stem cells (iPSCs) provide a new source of therapeutic cells free from the ethical issues or immune barriers of human embryonic stem cells. iPSCs also confer considerable advantages over conventional methods of studying human diseases. Since its advent, iPSC technology has expanded with 3 major applications: disease modeling, regenerative therapy, and drug discovery. Here we discuss, in a comprehensive manner, the recent advances in iPSC technology in relation to basic, clinical, and population health.

Keywords: drug discovery; human-induced pluripotent stem cells; macromedicine; micromedicine; personalized medicine.

Figure 1. Potential Applications of Patient-Specific iPSCs

Disease-specific target cells differentiated from patient-specific iPSCs have 3 major applications: disease modeling; regenerative therapies; and drug discovery/toxicity studies. iPSCs from patients with genetic mutations could be corrected via genome editing to yield healthy target cells for cell therapy. Both corrected and uncorrected target cells could be used for disease modeling or drug screening. iPSC = induced pluripotent stem cell; RBC = red blood cells.

Figure 2. Conventional Versus iPSC-based Drug Discovery

The conventional drug discovery pathway is a very inefficient process with a high attrition rate. The majority of drug candidates never reach the market due to safety and efficacy issues. This is partly attributed to the lack of appropriate drug development models that could accurately predict drug efficacy, and partly due to dependence on animal models of disease that do not replicate human pathophysiology. By comparison, iPSC technology allows high-throughput screening of therapeutic molecules by providing disease-specific drug development models that are generated from the patients themselves. This makes iPSC technology a much better predictive tool, and allows well-informed decisions to be made earlier in the drug development process. FDA = Food and Drug Administration; iPSC = induced pluripotent stem cell; iPSC-CM = induced pluripotent stem cell-derived cardiomyocyte.

Central Illustration: iPSC Clinical Trial: From Micromedicine to Macromedicine

iPSC technology has contributed to both micromedicine and macromedicine. This includes disease modeling and drug development on the basis of cellular and molecular analyses of individual patients to iPSC clinical trials for stratification on the basis of cellular and molecular analyses of a cohort of patients. Importantly, it could allow a more precise clinical trial by identifying a subset of patients with a specific disease who optimally respond to the drugs under investigation, thereby boosting success rates by pre-selecting these drug responders. DNA = deoxyribonucleic acid; iPSC = induced pluripotent stem cell; iPSC-CM = induced pluripotent stem cell-derived cardiomyocyte; RNA = ribonucleic acid.