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Review
. 2020 Jul;1471(1):18-56.
doi: 10.1111/nyas.14012. Epub 2019 Mar 15.

Human pluripotent stem cell-derived models and drug screening in CNS precision medicine

M Catarina Silva  1 , Stephen J Haggarty  1
Affiliations
Review

Human pluripotent stem cell-derived models and drug screening in CNS precision medicine

M Catarina Silva et al. Ann N Y Acad Sci. 2020 Jul.

Abstract

Development of effective therapeutics for neurological disorders has historically been challenging partly because of lack of accurate model systems in which to investigate disease etiology and test new therapeutics at the preclinical stage. Human stem cells, particularly patient-derived induced pluripotent stem cells (iPSCs) upon differentiation, have the ability to recapitulate aspects of disease pathophysiology and are increasingly recognized as robust scalable systems for drug discovery. We review advances in deriving cellular models of human central nervous system (CNS) disorders using iPSCs along with strategies for investigating disease-relevant phenotypes, translatable biomarkers, and therapeutic targets. Given their potential to identify novel therapeutic targets and leads, we focus on phenotype-based, small-molecule screens employing human stem cell-derived models. Integrated efforts to assemble patient iPSC-derived cell models with deeply annotated clinicopathological data, along with molecular and drug-response signatures, may aid in the stratification of patients, diagnostics, and clinical trial success, shifting translational science and precision medicine approaches. A number of remaining challenges, including the optimization of cost-effective, large-scale culture of iPSC-derived cell types, incorporation of aging into neuronal models, as well as robustness and automation of phenotypic assays to support quantitative drug efficacy, toxicity, and metabolism testing workflows, are covered. Continued advancement of the field is expected to help fully humanize the process of CNS drug discovery.

Keywords: drug discovery; human-induced pluripotent stem cells; neurodegenerative disorders; neuroscience; psychiatric disorders; screening.

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Conflict of interest statement

Competing Interests

SJH is a scientific advisory board member of Rodin Therapeutics, Psy Therapeutics, and Frequency Therapeutics. None of these entities were involved in manuscript preparation.

Figures

Figure 1.
Figure 1.
CNS research integrative approaches, between longitudinal clinical phenotyping information (top left, images from Ghetti et al. 2015), post-mortem brain pathology data (top right, images from Marquié et al. 2015) and patient iPSC-derived cellular models and research (bottom middle). Patient iPSC-derived cell models are a tool in the study of early disease molecular and cellular mechanisms, and therefore translational research. Results interpretation in the context of clinical and pathological data allows discerning the most relevant phenotypes, identification of biomarkers for pre-clinical and clinical diagnostics, as well as therapeutics development. Patient stratification based on clinical, pathological and iPSC molecular and cellular data aids in determining drug screening targets in defined subpopulations and may increase overall clinical trials success.
Figure 2.
Figure 2.
Proposed research pipeline, from human ex vivo models to in human clinical trials, with the goal of implementing human testing as early as possible. Patient-derived disease models focus on endogenous physiologically relevant proteins and molecular pathways, with associated genetic context. Coupled with extensive phenotypic analysis and validation across an increasing number of cell lines, iPSC-derived cells will have an important role in clinical diagnostics and identification of biomarkers that can guide drug screening as well as patient stratification for clinical trials. Most remarkably, iPSC-derived cells show increasing potential for small-molecule screening and secondary testing of novel therapeutics’ efficacy, toxicity and mode of action, in a human context and in advance of animal testing and human clinical trials. Novel human 3D models of BBB and organoids tissues like liver and kidneys may also be implemented in place of animal testing for PK/PD analysis. Predicted drug success vs. failure based on correlations derived from ex vivo cell models and patient-response will undoubtedly contribute to precision medicine efforts.
Figure 3.
Figure 3.
Summarized, non-exhaustive, schematic of the current landscape for human iPSC-derived or directed differentiation of somatic cells into neurons in 2D and 3D culture formats.
Figure 4.
Figure 4.
Phenotypic platforms for human iPSC-derived neuronal models. Optimization and quality control (QC) of CNS cell model derivation paired with development and integration of standardized phenotypic pipelines, including genetic, biochemical, proteomic and toxicity analysis of neurons ex vivo, for determining molecular mechanisms of disease. Organoid image adapted from sciencenews.org 2018.
See this image and copyright information in PMC

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