Year: 2020
Type: editorial
Abstract: Induced pluripotent stem cells (iPSCs) are mature, differentiated cells that have been genetically reprogrammed to regain a cardinal feature of embryonic stem cells: the ability to re-differentiate into any cell or tissue type in the body. The now-well-established methods of “de-differentiation” enable scientists to transform accessible cells, such as white blood cells or skin fibroblasts, into patient-specific cell lines for even the most hard-to-biopsy tissues, such as the brain and heart. The discovery of human iPSCs in 2007 has fostered novel insights into conditions spanning etiologies and organ systems, from Alzheimer’s disease to Zellweger spectrum disorder.1-3 The hope is that the insights gained from these patient-derived cells will benefit patients through new and improved therapeutics. The field of Clinical Pharmacology has incorporated iPSCs to move that hope toward clinical reality; iPSCs have been used as model systems to understand disease pathology and identify potential therapies (Figure 1). It has been advocated that integration of iPSCs into “organ-on-a-chip” systems will not only improve translatability of drug discovery but will become a diagnostic technology for understanding clinical pharmacology variability and enabling precision medicine.4, 5 In a recent issue of Clinical Pharmacology and Therapeutics, Maciel et al. used iPSC-derived spinal motor neurons from patients with the neurodegenerative disorder Charcot-Marie-Tooth (CMT) disease.6 The iPSCs were cultured as three-dimensional spheroids. Spheroids derived from patients with a specific N98S variant in the NEFL gene had axonal neurofilament deposits that were not observed in control cells derived from those without CMT or with CMT due to a different NEFL variant. The spheroids were then used to test kinase inhibitors for their potential therapeutic effect, identifying two classes of kinase inhibitors that reversed axonal neurofilament accumulation. Thus, iPSC-derived spheroids were demonstrated to be an excellent model system to explore the pathophysiology of CMT and to test potential therapies for this disease. In addition to providing insights to the diseases, iPSCs have been used as “canaries in the coal mine” for early identification of potential drug toxicity. For example, given the known increased incidence of neuropathic side effects to anticancer drugs among patients with CMT, Ohara et al. used iPSCs from patients with CMT to detect compounds that may contribute to neurotoxicity.7 Similarly, Blanchette et al. used population-based iPSC-derived cardiomyocyte models to predict cardiotoxicity, and suggest that iPSCs may be used to conduct the required preclinical “Thorough QT/QTc” studies in a dish.8 These studies leverage genetic susceptibility to develop sensitive screening assays, which may benefit large and diverse patient populations with a myriad of diseases. In this issue of Clinical Pharmacology and Therapeutics, Genova et al. demonstrate another use for iPSCs.9 In this work, iPSCs were generated from patients with the related disorders of immunity ataxia telangiectasia and Aicardi–Goutières syndrome. Neither disease currently has a cure, and available therapies have variable efficacy in treating symptoms. The iPSC lines from affected patients and controls were treated with a battery of immunomodulatory therapies, with careful assessment of biomarkers to determine response. Of particular interest are the observed differences in response to various therapies based on the specific disease (and even disease subtype) of the affected patient. These findings demonstrate the potential for iPSCs to provide a patient-specific assay of drug efficacy, allowing truly personalized and precision therapy. This novel approach may be specifically impactful in rare disease drug development, given the very limited number of clinical subjects.10 Since the discovery of iPSCs, the laboratory techniques used to de-differentiate, re-differentiate, and assay these cells to test important, clinically relevant hypotheses have evolved and matured. New technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR) gene editing have been applied to further enhance the scientific and therapeutic potential of these cells. With continued innovation, more new technologies will continue to be applied, enhancing the use of iPSC for discovery and accelerating those discoveries toward implementation in patient care.
DOI: 10.1002/cpt.1924
Authors: Sara L. Van Driest, Piet H. van der Graaf
Institutions: Vanderbilt University Medical Center, Leiden University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W3043118032