Elsevier

Advanced Drug Delivery Reviews

Volumes 69–70, 20 April 2014, Pages 170-178
Advanced Drug Delivery Reviews

Exploiting pluripotent stem cell technology for drug discovery, screening, safety, and toxicology assessments☆

https://doi.org/10.1016/j.addr.2013.11.012Get rights and content

Abstract

In order for the pharmaceutical industry to maintain a constant flow of novel drugs and therapeutics into the clinic, compounds must be thoroughly validated for safety and efficacy in multiple biological and biochemical systems. Pluripotent stem cells, because of their ability to develop into any cell type in the body and recapitulate human disease, may be an important cellular system to add to the drug development repertoire. This review will discuss some of the benefits of using pluripotent stem cells for drug discovery and safety studies as well as some of the recent applications of stem cells in drug screening studies. We will also address some of the hurdles that need to be overcome in order to make stem cell-based approaches an efficient and effective tool in the quest to produce clinically successful drug compounds.

Section snippets

Introduction: rationale for use of stem cells for drug screening

Drug development is a multi-year, multi-million dollar proposition with the vast majority of promising compounds failing to come to fruition. Failure is likely not due to a lack of testable compounds as chemical libraries contain thousands of potentially therapeutic agents just waiting to be explored and scrutinized. Drug screening using in vitro cell culture systems provides the pharmaceutical industry a means to narrow down these large chemical libraries into a list of candidate compounds for

Targeted approach to drug discovery

Targeted and phenotypic approaches are two distinct methods for the identification of drug leads (Fig. 2; Table 1). A targeted approach focuses on identifying drugs that can interact with genes, gene products or molecular mechanisms [15], [16]. Therefore, a target based approach relies on what is known about a specific disease, and often requires that a specific mode of action is known, which is generally through the activation or inhibition of a receptor or channel (Fig. 2). The goal of a

Stem cells in safety pharmacology

The pharmaceutical industry generates large libraries of new chemical entities each year with the intent on identifying drugs that either interact with a chemical target or induce a desired physiological effect. When effective drugs are identified, further preclinical safety screening is necessary, both for the safety of the patients and to avoid large costs associated with failed clinical trials. Yet, even after exhaustive safety screening for proper adsorption, distribution, metabolism and

Disease modeling and drug screening

Much work has gone into identifying disease relevant defects in iPSC derived models that can be targeted for drug screening efforts. To date, most advances in cardiomyocyte drug screening have come in the form of toxicity screening rather than lead identification for specific cardiac related disease. However, iPSC derived cardiomyocytes have been used to evaluate the therapeutic efficacy potential of new and existing pharmacological agents. For example, Itzhake et al. generated iPSCs from

Challenges to PSC implementation in drug development

As demonstrated above many academic and industry laboratories have made substantial efforts toward developing systems for modeling human disease, exploring novel treatment paradigms, and testing the safety of current drugs using human PSCs. Despite these advances and the great promise PSC model systems provide, there is still much work to do. Some of the challenges moving forward include: 1) reducing cost, 2) standardizing HTS/HCS by reducing differentiation variability and enriching specified

Conclusions

The development of iPSC technology spurred the use of PSCs in disease modeling and drug exploration. As scientists begin to better understand the use of these cells and develop more reliable methods for differentiation, modeling, and screening, PSCs will likely aid the drug discovery process and reduce attrition rates. Though one must be aware of the challenges and caveats of using PSCs, recent advances and proof of concept retrospective studies provide the framework for improvements in drug

Acknowledgments

The authors thank Teresa Patitucci for providing artistic talent for figures and graphical abstract.

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    ☆

    This review is part of the Advanced Drug Delivery Reviews theme issue on “Innovative tissue models for drug discovery and development”.

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