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 h… Show more
“…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.…”
Section: Scientifi C Prerequisites For Clinical Testing and Usementioning
“…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.…”
Section: Scientifi C Prerequisites For Clinical Testing and Usementioning
“…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 Currently failures of drug candidates identified in initial screens leads to an estimated one-third of drugs being withdrawn from the market and the expenditure lost as a consequence has left the drug development industry sore [3].…”
Section: Cardiovascular Disease: the Need For Change In The Drug Indumentioning
confidence: 99%
“…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].…”
Section: Cardiovascular Disease: the Need For Change In The Drug Indumentioning
confidence: 99%
“…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).…”
Section: Current Applications Of Human Pluripotent Stem Cells In Drugmentioning
Cardiovascular disease (CVD) is an alarming health problem responsible for a large percentage of fatality worldwide. Current treatment is limited and research is ongoing to address this serious health problem. As mortality rates rise, the demand for novel therapeutics has pressed the pharmaceutical industry to explore alternative approaches for CVD drug development. Human pluripotent stem cells (hPSCs) hold great promise in bringing new effective cardiovascular treatments to the market through providing an improved testing platform for pre-clinical drug screening. Both stem cells derived from pre-implantation human embryos or somatic cells by reprogramming are under intense investigation for their potentially valuable attributes of cell renewal and pluripotency. This approach aims to overcome the lack of appropriate human cardiac disease models for toxicology testing by providing a novel system that is scalable, reproducible and from an inexhaustible source. Here we review the opportunities for cardiomyocytes derived from human stem cells in the field of cardiovascular drug development.
“…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.…”
The somatic epigenome can be reprogrammed to a pluripotent state by a combination of transcription factors. Altering cell fate involves transcription factors cooperation, epigenetic reconfi guration, such as DNA methylation and histone modification, posttranscriptional regulation by microRNAs, and so on. Nevertheless, such reprogramming is inefficient. Evidence suggests that during the early stage of reprogramming, the process is stochastic, but by the late stage, it is deterministic. In addition to conventional reprogramming methods, dozens of small molecules have been identifi ed that can functionally replace reprogramming factors and signifi cantly improve induced pluripotent stem cell (iPSC) reprogramming. Indeed, iPS cells have been created recently using chemical compounds only. iPSCs are thought to display subtle genetic and epigenetic variability; this variability is not random, but occurs at hotspots across the genome. Here we discuss the progress and current perspectives in the fi eld. Research into the reprogramming process today will pave the way for great advances in regenerative medicine in the future.
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