Induced pluripotent stem cells in disease modelling and drug discovery

Abstract

The derivation of induced pluripotent stem cells (iPSCs) over a decade ago sparked widespread enthusiasm for the development of new models of human disease, enhanced platforms for drug discovery and more widespread use of autologous cell-based therapy. Early studies using directed differentiation of iPSCs frequently uncovered cell-level phenotypes in monogenic diseases, but translation to tissue-level and organ-level diseases has required development of more complex, 3D, multicellular systems. Organoids and human-rodent chimaeras more accurately mirror the diverse cellular ecosystems of complex tissues and are being applied to iPSC disease models to recapitulate the pathobiology of a broad spectrum of human maladies, including infectious diseases, genetic disorders and cancer.

Figure 1.. Progress in iPSC-based therapies.

Upon the discovery of iPSCs, approaches to cell-based therapy and drug discovery were proposed. Here, we illustrate the progress made toward these goals in the past decade. Iterative improvements in reprogramming methodologies have increased the efficiency of iPSC derivation and the quality of iPSC lines in use. As a stride toward autologous iPSC-based therapy, gene editing using CRISPR–Cas9 technology has been widely applied to iPSCs to enable repair of disease-causing genetic lesions. As discussed in this review, remarkable advances have been made approaches to in directed differentiation that can be used to derive gene-corrected terminally differentiated cells. However, with rare exceptions, widespread autologous iPSC-based cell therapy remains out of reach. Optimization of transplantation and directed differentiation in chimaeric models as well as improvement in the efficiency and scalability of generating clinical-grade cells will continue to advance toward the goal of autologous therapy in varied organ systems. Non-corrected cells differentiated from patient-derived iPSCs have been used in drug screening and validation studies largely using cell-level readouts. Currently, a handful of candidate drugs identified in iPSC-based systems are under study in human trials. We anticipate that increased sophistication of iPSC-based disease models using organoids will integrate into these approaches to drug discovery by improving preclinical drug screening, design and validation using highly disease-relevant readouts to accelerate candidate therapies into clinical trials. Figure adapted with permission from Ref. .

Figure 2.. Application of iPSC-derived organoids to disease modelling and drug discovery.

Remarkable progress has been made in the differentiation of increasingly complex multicellular and diverse organoid systems across many tissues. We propose that parallel differentiation of organoids from patient-derived iPSCs as well as genetically corrected, isogenic control iPSCs will allow attribution of an organoid-level disease phenotype to a specific molecular lesion. Once a clear organoid-level readout is established, diseased organoids can be used in drug screening and validation studies.

Figure 3.. iPSC-based chimaeric models.

Summary of the current state of human iPSC chimaera models, illustrating the diversity of tissues and organs modelled as chimaeras and the classes of disease that have been modelled in chimaeras.