Contribution of Human Pluripotent Stem Cell-Based Models to Drug Discovery for Neurological Disorders

Abstract

One of the major obstacles to the identification of therapeutic interventions for central nervous system disorders has been the difficulty in studying the step-by-step progression of diseases in neuronal networks that are amenable to drug screening. Recent advances in the field of human pluripotent stem cell (PSC) biology offers the capability to create patient-specific human neurons with defined clinical profiles using reprogramming technology, which provides unprecedented opportunities for both the investigation of pathogenic mechanisms of brain disorders and the discovery of novel therapeutic strategies via drug screening. Many examples not only of the creation of human pluripotent stem cells as models of monogenic neurological disorders, but also of more challenging cases of complex multifactorial disorders now exist. Here, we review the state-of-the art brain cell types obtainable from PSCs and amenable to compound-screening formats. We then provide examples illustrating how these models contribute to the definition of new molecular or functional targets for drug discovery and to the design of novel pharmacological approaches for rare genetic disorders, as well as frequent neurodegenerative diseases and psychiatric disorders.

Identification of signaling pathways modifying human dopaminergic neuron development using a pluripotent stem cell-based high-throughput screening automated system: purinergic pathways as a proof-of-principle

“…Moreover, our tool can be used to identify therapeutic molecules for various diseases affecting DA circuit development and plasticity, which are agnostic to the molecular mechanisms involved in disease emergence and progression. This is of particular interest for rare or multifactorial diseases ( Benchoua et al, 2021 ). It can also aid in the identification of disease-modifying pathways and genes at high throughput using CRISPR/CAS9-based whole-genome screening to provide insights into disease etiology ( Nishiga et al, 2021 ).…”

In vitro human cell culture models in a bench‐to‐bedside approach to epilepsy

“…Another potential use of iPSCs is a high‐throughput screening of candidate molecules (for a review see Ref. [ 114 ]). Disease models based on iPSCs are more commonly used for early‐onset diseases than for late‐onset diseases.…”

Neuropharmacology of human TERA2.cl.SP12 stem cell-derived neurons in ultra-long-term culture for antiseizure drug discovery

“…Successful isolation and culture of human embryonic stem (ES) cells by Thomson et al (1998) and later, induced pluripotent stem (iPS) cells by Yamanaka et al (2007) gave rise to great excitement and optimism that they could be exploited in regenerative medicine, disease modeling and drug discovery ( Gearhart, 1998 ; Gunaseeli et al, 2010 ; Hoang et al, 2022 ; Kim et al, 2022 ). Since these milestone discoveries, significant progress has been made delineating protocols and culture conditions to create specific tissues from ES and iPS cells, especially for different types of human neurons and glia, including hippocampal, hypothalamic, cortical, and spinal neurons, as well as for oligodendrocytes, astrocytes and microglia ( Benchoua et al, 2021 ). Initial evaluation of neurons from human pluripotent stem cells were often limited to protein and gene expression data, along with morphological changes in the differentiated cells ( Halliwell, 2017 ).…”

“…Incorporation of pluripotent stem cell-derived neurons in drug screening has now been reported for a variety of genetic diseases such as Fragile-X Syndrome ( Urbach et al, 2010 ; Sheridan et al, 2011 ), neurodegenerative diseases including Alzheimer’s disease ( Arber et al, 2017 ) and psychiatric disorders such as depression and schizophrenia (reviewed by Benchoua et al, 2021 ). Stem cell derived neurons utilized in such studies, however, are relatively immature and maintained in culture for only short periods of time (often days to a few weeks) and may not always represent mature neurons which can take many months to achieve ( Halliwell, 2017 ; Sharlow et al, 2020 ).…”