Approach to Neurotoxicity using Human iPSC Neurons: Consortium for Safety Assessment using Human iPS Cells
Takafumi Shirakawa1, Ikuro Suzuki1
1Consortium for Safety Assessment using Human iPS Cells (CSAHi), Neuro Team, Japan.
Abstract:
Neurotoxicity, as well as cardiotoxicity and hepatotoxicity, resulting from administration of a test article is considered a major adverse effect both pre-clinically and clinically. Among the different types of neurotoxicity occurring during the drug development process, seizure is one of the most serious one. Seizure occurrence is usually assessed using in vivo animal models, the Functional Observational Battery, the Irwin test or electroencephalograms. In in vitro studies, a number of assessments can be performed using animal organs/cells. Interestingly, recent developments in stem cell biology, especially the development of Human-Induced Pluripotent Stem (iPS) cells, are enabling the assessment of neurotoxicity in human iPS cell-derived neurons. Further, a Multi-Electrode Array (MEA) using rodent neurons is a useful tool for identifying seizure-inducing compounds. The Consortium for Safety Assessment using Human iPS Cells (CSAHi; http://csahi.org/en/) was established in 2013 by the Japan Pharmaceutical Manufacturers Association (JPMA) to verify the application of human iPS cell-derived neuronal cells to drug safety evaluation. The Neuro Team of CSAHi has been attempting to evaluate the seizure risk of compounds using the MEA platform. Here, we review the current status of neurotoxicity and recent work, including problems related to the use of the MEA assay with human iPS neuronal cell-derived neurons, and future developments.
Insights
Assessing drug-induced neurotoxicity, particularly seizures, is crucial. Human induced pluripotent stem (iPS) cell-derived neurons with Multi-Electrode Array (MEA) offer a promising in vitro approach for safety evaluation.
Area of Science:
- Neuroscience
- Toxicology
- Stem Cell Biology
Background:
- Drug development faces challenges with major adverse effects like neurotoxicity, cardiotoxicity, and hepatotoxicity.
- Seizures represent a serious form of neurotoxicity frequently assessed via in vivo animal models.
- In vitro methods using animal cells exist, but human-specific models are advancing drug safety.
Purpose of the Study:
- To review the current status of neurotoxicity assessment in drug development.
- To explore the application of human induced pluripotent stem (iPS) cell-derived neurons for evaluating seizure risk.
- To discuss the utility and challenges of the Multi-Electrode Array (MEA) assay with human iPS cells.
Main Methods:
- Review of existing literature on neurotoxicity assessment methods (in vivo and in vitro).
- Focus on the development and application of human iPS cell-derived neurons.
- Utilizing the Multi-Electrode Array (MEA) platform for seizure detection in neuronal networks.
Main Results:
- Human iPS cell-derived neurons provide a viable in vitro model for neurotoxicity studies.
- The MEA assay demonstrates potential for identifying seizure-inducing compounds using human iPS cells.
- Challenges remain in optimizing MEA assays with human iPS neuronal cells for reliable safety evaluation.
Conclusions:
- Human iPS cells are advancing in vitro neurotoxicity testing, offering human-specific insights.
- The MEA platform holds promise for predicting seizure risk during preclinical drug development.
- Further research is needed to refine MEA assays with human iPS cells for robust drug safety assessment.
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