Integrating Human Pluripotent Stem Cells into Drug Development

Abstract

Integration of physiologically relevant in vitro assays at the earliest stages of drug discovery may improve the likelihood of successfully translating preclinical discoveries to the clinic. Assays based on in vitro-differentiated, human pluripotent stem cell (IVD hPSC)-derived cells, which may better model human physiology, are starting to impact the drug discovery process, but their implementation has been slower than originally anticipated. In this Perspective, we discuss imperatives for incorporating IVD hPSCs into drug discovery and the associated challenges.

Ethics and Policy Issues for Stem Cell Research and Pulmonary Medicine

“…43 Th ree-dimensional lung models have been constructed using a combination of stem cells, tissue engineering, biomaterials (to mimic the lung extracellular environment), and bioreactors (to mimic physiologic lung conditions and generate shear stress, pulsatile airfl ow, and an air-liquid interface). Of particular interest in this regard are microfl uidic devices and microscale "organ-on-chip" technologies, which can incorporate stem cell-derived lung tissue to reconstitute organ-level lung functions on microchips.…”

Human pluripotent stem-cell-derived cardiomyocytes in cardiovascular drug discovery and development

“…However this reductionist approach, of one-target one-drug oneeffect paradigm, is associated with numerous flaws [2]. Currently failures of drug candidates identified in initial screens leads to an estimated one-third of drugs being withdrawn from the market and the expenditure lost as a consequence has left the drug development industry sore [3].…”

“…This offers an explanation as to why the efficacy of translating successful in vitro drug candidates into clinical trials has yielded disappointing outcomes -<10% of compounds that enter the clinical phase of testing achieve market approval, with estimated costing of $1.2-1.7 billion per drug [4]. However, the drug industry is undergoing radical change and is moving away from this so called reductionist approach and embracing new potentials [2].…”

“…Numerous proof-of-principle examples of late have been reported of IVD hPSC-cells from patients with monogenic disorders or engineered disease gene mutations recapitulating disease phenotypes in vitro [2]. The first studies aimed at modelling cardiac diseases using this approach were monogenic channelopathies, including different subtypes of long QT syndrome or cathecholaminergic polymorphic ventricular tachycardia (CPVT).…”

Toward pluripotency by reprogramming: mechanisms and application

“…The most rigorous way to study the effects of genetic variants in human disease would be the generation of isogenic iPSCs, which differs only in the mutation and has the same genetic background. These disease-specific iPS cells and isogenic control cells would also enable screening for novel drugs (Engle and Puppala, 2013). In addition, human disease cell types derived from iPSCs would be more relevant for toxicological testing during the drug development process, compared with the established cancer origin cell types or animal models used now.…”