Abstract
Human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and human-induced pluripotent stem cells (hiPSCs), have the potential to accelerate the drug discovery and development process. In this review, by analyzing each stage of the drug discovery and development process, we identified the active role of hPSC-derived in vitro models in phenotypic screening, target-based screening, target validation, toxicology evaluation, precision medicine, clinical trial in a dish, and post-clinical studies. Patient-derived or genome-edited PSCs can generate valid in vitro models for dissecting disease mechanisms, discovering novel drug targets, screening drug candidates, and preclinically and post-clinically evaluating drug safety and efficacy. With the advances in modern biotechnologies and developmental biology, hPSC-derived in vitro models will hopefully improve the cost-effectiveness and the success rate of drug discovery and development.
Highlights
HPSCs show the potential to generate all lineages of the embryo in vivo and can differentiate into all types of somatic cells in vitro, becoming a popular and valuable cellular source for the treatment of many degenerative diseases, including Parkinson’s disease (PD), Alzheimer’s disease (AD), and age-related macular degeneration (AMD) [3], as well as injuries to tissues lacking regeneration capability such as ischemic heart failure [4], diabetes, and spinal cord injuries [5]
Contrary to focusing on a particular application or disease, we present the potential of Human pluripotent stem cells (hPSCs)-derived models during the whole process of drug discovery and development
They constructed a mathematical AD signaling model integrating relevant pathways validated with iCOs, which are cerebral organoids differentiated from human-induced pluripotent stem cells (hiPSCs) and built a high-content screening system using 1300 organoids from
Summary
The drug discovery pipeline involves several stages. The first is to use a certain target, a phenotypic screening method or a target-based screening method, to pick up one or more candidate molecules, which are called lead compounds or leads. Lead discovery in target-based and phenotypic screening are usually based on immortalized cells, and evaluating efficacy and safety in preclinical trials are generally based on immortalized cells, primary cells, and animal models. As an alternative to animal models and primary cells, hPSC technology has caused a radical change in the field of drug discovery and clinical trials. Allowing for generating disease- and patient-specific functional somatic cells in a large scale, hPSC technology can avoid many problems that usually accompany animal and primary cell models. Following success in preclinical studies, the selected compound enters the stage of clinical trials, which include phases I, II, and III. To achieve the goal, promoting efficiency and accuracy of drug screening and eliminating potential toxic and/or ineffective compounds before entering clinical trials are urgently needed. With similar features to primary cell types and higher accessibility [28,29] in combination with technologies such as 3D cell cultures, organoid technology, and microfabrication, hPSCderived functional somatic cells are promising in offering more accurate disease models
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