In vitro Models for Seizure-Liability Testing Using Induced Pluripotent Stem Cells

Abstract

The brain is the most complex organ in the body, controlling our highest functions, as well as regulating myriad processes which incorporate the entire physiological system. The effects of prospective therapeutic entities on the brain and central nervous system (CNS) may potentially cause significant injury, hence, CNS toxicity testing forms part of the “core battery” of safety pharmacology studies. Drug-induced seizure is a major reason for compound attrition during drug development. Currently, the rat ex vivo hippocampal slice assay is the standard option for seizure-liability studies, followed by primary rodent cultures. These models can respond to diverse agents and predict seizure outcome, yet controversy over the relevance, efficacy, and cost of these animal-based methods has led to interest in the development of human-derived models. Existing platforms often utilize rodents, and so lack human receptors and other drug targets, which may produce misleading data, with difficulties in inter-species extrapolation. Current electrophysiological approaches are typically used in a low-throughput capacity and network function may be overlooked. Human-derived induced pluripotent stem cells (iPSCs) are a promising avenue for neurotoxicity testing, increasingly utilized in drug screening and disease modeling. Furthermore, the combination of iPSC-derived models with functional techniques such as multi-electrode array (MEA) analysis can provide information on neuronal network function, with increased sensitivity to neurotoxic effects which disrupt different pathways. The use of an in vitro human iPSC-derived neural model for neurotoxicity studies, combined with high-throughput techniques such as MEA recordings, could be a suitable addition to existing pre-clinical seizure-liability testing strategies.

Role of Human-Induced Pluripotent Stem Cell-Derived Spinal Cord Astrocytes in the Functional Maturation of Motor Neurons in a Multielectrode Array System

“…Multielectrode arrays (MEA) are particularly suited for these purposes as they enable the recording of large populations of neurons and their network activity, and have the potential to inform about neuron–glia interactions. This is achieved through the detection of extracellular voltages, which reflect the spike activity of local neuronal populations.…”

Ovine fetuses from slaughterhouses: a useful source for neural cell primary cultures

“…Indeed, the favorite animal models are those showing brain size, brain complexity, life span expectancy and diseases similar to those of humans [31, 32]. Human-derived cell cultures exist, including stem cell-derived primary neuronal and glial cultures, as well as sophisticated 3D organoids [23,24,25]. However, cultures from lots of animal species are also exploited as validated models.…”

“…Cell cultures carried out from sheep brain represent another important tool for studying neural cell biology instead of the usual cell cultures obtained from rats [18, 19, 20, 21, 22]. Actually, in addition to ovine cultured cells, human-derived cell models exist, including stem cell-derived primary neuronal and glial cultures, as well as sophisticated 3D organoids [23, 24, 25]. However, such models may be expensive and/or need a high degree of manipulation in order to get differentiated neural cells.…”

Development of two-photon polymerised scaffolds for optical interrogation and neurite guidance of human iPSC-derived cortical neuronal networks

“…[4][5][6][7] To determine relevant functional human mechanisms and their disease related dysfunction it is therefore becoming clear that patient-derived human cell models are required that allow functional interrogation of cell-cell interactions from single cells to the whole-network level. [8][9][10][11][12][13][14] The last decade has seen the emergence of neuronal cultures derived from human induced pluripotent stem cells (iPSCs) that has promise to be a technology that addresses many of the major issues currently facing the field. Neuronal cultures derived from iPSCs retain the disease genotype of the original donor, and therefore present a highly relevant model.…”