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

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.

Discovery of suppressors of CRMP2 phosphorylation reveals compounds that mimic the behavioral effects of lithium on amphetamine-induced hyperlocomotion

“…To confirm and extend these MS-based proteomic findings with CHIR-99021, and to determine if they could be also observed with the much less potent, but clinically 43 were significantly regulated by 10 μM CHIR-99021 (dots above dashed line-blue and brown dots). Green dots represent phosphopeptides mapped to CRMP2 protein, while red dots to GSK3α/β.…”

“…Human induced pluripotent stem cell (hiPSC) technology is being used increasingly to create genetically accurate cellular models of diseases, including neuropsychiatric disorders, whether monogenic (e.g., Fragile X syndrome and Rett syndrome [34][35][36] or genetically more complex (e.g., schizophrenia 37,38 and BD [39][40][41] ). In addition to human disease modeling, an exciting opportunity presented by hiPSC technology is the capacity to probe the cellular mechanism of action of drugs used to treat neuropsychiatric disorders and to develop highthroughput phenotypic assays for novel therapeutic discovery 42,43 . For these reasons, we and others have developed neural models through the derivation of homogenous, self-renewing, cultures of neural progenitor cells (NPCs) from hiPSCs 34,[44][45][46] .…”

TSC patient-derived isogenic neural progenitor cells reveal altered early neurodevelopmental phenotypes and rapamycin-induced MNK-eIF4E signaling

“…Further, the inability to establish expandable human cell lines derived from various TSC-associated lesions, along with genetically matched control cell lines has made it difficult to define the precise pathogenic mechanisms involved in TSC. Patient-specific induced pluripotent stem cells (iPSCs) derived from somatic cells, followed by differentiation into specific cell types, are rapidly evolving to be powerful for disease modeling to study pathophysiology and to identify treatments [13][14][15][16][17]. More importantly, the emergence of powerful genome editing techniques has made it possible to generate isogenic pairs of disease and control human iPSCs that differ only with respect to disease-causing gene mutations [18][19][20].…”

Exifone is a Potent HDAC1 Activator with Neuroprotective Activity in Human Neuronal Models of Neurodegeneration

“…Patient iPSC-derived neuronal cell models can recapitulate specific disease-relevant phenotypes and are increasingly recognized as robust systems for drug discovery 22 . To evaluate the neuroprotective capabilities of exifone in a neurodegenerative diseaserelevance context, we employed an iPSC-derived neuronal cell model from an FTD patient harboring a tau-A152T variant that shows an early accumulation of tau protein in the form of phospho-tau species of reduced solubility, and as a consequence exhibits selective vulnerability to stress 23 .…”