Leveraging Human Pluripotent Stem Cells for Breakthroughs in Drug Discovery for Neuroscience

This blog post was written by STEMCELL Technologies, which provides cell isolation products, specialized cell culture media, primary cells and supporting reagents for use in life sciences research across the basic to translational research continuum. STEMCELL Technologies’ in-house Contract Assay Services (CAS) work with you to design and perform in vitro potency and safety studies for drug discovery and development. Their services are available on the Scientist.com marketplace.

Connect with STEMCELL Technologies on Scientist.com

Transforming the future of neurological therapeutics requires tools as powerful as the scientific vision driving the research and development. Due to the difficulty of obtaining human brain tissue for experimental studies, animal models have traditionally been popular tools for neurological disease modeling and therapeutic evaluation. In recent years, human pluripotent stem cells (hPSCs) have enabled biotech companies to take more representative approaches and develop more predictive models for drug discovery and human neurological disease research. As a company of Scientists Helping Scientists, STEMCELL Technologies provides tools and expertise that support researchers in accelerating the pace of discovery. In this post, explore examples of hPSC-derived neural models used for disease modeling, drug efficacy and toxicity testing, as well as ADME applications and discover tools from STEMCELL Technologies that have enabled these experiments.

Why Use hPSC-Derived Neural Model Systems

hPSC-derived neural models provide a more accurate and relevant alternative to traditional animal models and simpler in vitro models. hPSCs are self-renewing, multipotent cells and so can be differentiated into neural cells, including neurons and glia, as well as organoids. These hPSC-derived neural models, from cultures of single cell types to 3D organoids and co-cultures, stand out for their ability to effectively recapitulate aspects of human neural physiology, providing an essential platform for understanding the complexities of neurological diseases and developing effective treatments.

Drug developers who make faster and more reliable decisions early in the therapeutic development process can mitigate the high costs associated with late-stage clinical trial failures due to discrepancies in drug effects between non-human models and actual human outcomes. The physiological relevance of these advanced hPSC-derived models enables drug developers to make decisions using more predictive data. hPSC-derived neural disease models allow for detailed investigations into a treatment’s toxicity and physiological interactions within a context that closely mimics human neural tissue, using cells that are either patient-derived or genetically engineered to replicate human cellular diversity. Furthermore, these models provide comprehensive data that enable informed decision-making throughout the drug development process. This can address the high rate of drug attrition and enhance the likelihood of clinical success by identifying therapeutic effects early on and providing the confidence needed to advance therapeutic candidates into clinical trials.

Biotech companies looking for models that are both scalable and compatible with automation to efficiently screen a large number of compounds and optimize drug testing conditions can also use hPSC-derived neural models to accelerate the process of identifying therapeutic candidates. Ultimately, integrating hPSC-derived neural models into drug development pipelines enables significantly more cost-effective and efficient processes, providing earlier, confident insights that minimize resource-intensive late-stage testing and reduce the overall investment required for successful drug discovery.

How hPSCs Have Enhanced Drug Discovery

With fewer than 10% of the compounds that enter Phase I clinical trials being approved for clinical use, and more than 75% of these failures being due to efficacy and/or safety issues¹ , more predictive models are of paramount importance. From target discovery to preclinical testing, hPSC models are informing decisions rapidly, reliably and predictively.

Disease Models for Evaluating Therapeutic Targets and Drug Potency

hPSC-based neural workflows can be used to leverage patient-specific disease models to better predict drug efficacy and are/may be especially powerful for studying rare pathologies. For example, researchers from the University of Manitoba developed a clinical trial pre-screening platform to assess therapeutic effectiveness for patients with ultra-rare diseases using induced pluripotent stem cell (iPSC) models.² With human brain tissue being hard to come by, the ability to generate patient-specific differentiated cells from iPSCs offers unique potential. Using a controlled, patient-specific disease model context to evaluate drug candidates enables more informed decisions about lead selection.

To create a robust platform for assessing the efficacy and toxicity of the drug panel of interest, the development of a high-quality iPSC-derived neural model was crucial for this research. Researchers from the University of Manitoba used STEMdiff™ Forebrain Neuron Differentiation Kit for highly pure and efficient neural differentiation (Figure 1) of patient-derived iPSCs for enhanced reliability and reproducibility. Additionally, the team also used STEMdiff™ Forebrain Neuron Maturation Kit, which supports long-term neural cell culture maintenance and promotes neuronal activity, providing physiologically relevant results.

Assessing Neurotoxicity in Drug Candidates

Researchers from the Drug Safety Research & Evaluation team at Takeda Pharmaceuticals have investigated innovative methods to predict neurotoxicity during the lead optimization process. The team evaluated the application of an iPSC-derived 3D neural model as a high-throughput predictive assay and determined that the neural spheroids maintained high specificity in identifying human neurotoxicity concerns.³ Using iPSC-derived 3D models for lead optimization enables a reduction in the number of animals used to narrow down candidate compounds, as well as a more relevant model with human-specific cellular biology and genetics when assessing neurotoxicity.

The 3D neural spheroids were cultured in a physiologically relevant environment, using BrainPhys™ Neuronal Medium. Choosing a medium that supports long-term culture and enhances neuronal function is critical for accurately assessing neurotoxicity in drug candidates and achieving predictive results.

ADME (Absorption, Distribution, Metabolism and Excretion) Characterization and Optimization

Specialized 3D hPSC-derived models can recapitulate complex human-specific biology in ways that alternative models cannot. For example, hPSC-derived choroid plexus organoids develop physiological cystic structures that effectively mimic the complexity of the human blood-cerebrospinal fluid (CSF) barrier.⁴ This type of advanced model allows for a deeper understanding of the permeability of neuroactive drugs across this blood-CSF barrier for more relevant insights.

When using organoid models for performing drug screening, organoid reproducibility is critical to achieve reliable and translatable results. STEMdiff™ Choroid Plexus Organoid Differentiation Kit and STEMdiff™ Choroid Plexus Organoid Maturation Kit enable the generation of reproducible organoids with CSF-like fluid cysts, which can be maintained long-term for screening applications (Figure 2).

Standardized Tools for Successful In Vitro Drug Development

To obtain high-quality results with advanced hPSC-derived models, consistent hPSC differentiation is crucial. Without standardized hPSC culture conditions, even the most detailed and rigorously followed stem cell differentiation protocols may still lead to inconsistent differentiation.^5,6 STEMdiff™ is a line of culture medium kits specifically optimized for hPSC differentiation. Whether you’re looking to produce 2D neural cell types or 3D organoid models, there are standardized kits to reproducibly and efficiently differentiate embryonic stem and iPSC lines. These kits offer an easy-to-use workflow that’s accessible regardless of your level of hPSC culture experience, while still maintaining the benefits of consistency and physiological relevance.

One consideration with hPSC-based models is that these cells are inherently immature, a potential limitation when developing a predictive drug discovery model. To promote maturity in hPSC-derived neural systems, assessing physiologically relevant neural activity is important. With long-term culture, stronger and more coordinated network activity develops in hPSC-derived neural cultures, reflecting a more mature state. BrainPhys™ Neuronal Medium is a neurophysiological basal medium that promotes neuronal function and synaptic activity, enhancing the physiological relevance of hPSC-based neural models.⁷ Neural STEMdiff™ kits also integrate these benefits with BrainPhys™-based maturation media.

Evaluating the functional activity of neurons is another crucial readout for reliable studies of neurological diseases, drug responses and neurodevelopmental processes. The Maestro Pro™ multi-electrode array (MEA) system allows the convenient capture of live-cell activity across an entire population of cells. Non-invasive and label-free, this system enables long-term monitoring of electrophysiological maturation (Figure 5), as well as real-time recording of responses to experimental stimuli.

Streamlined and Adaptable hPSC Workflows

Adopting hPSC-based models is becoming increasingly accessible, even without hPSC culture experience. Cryopreserved cell products at various stages of neural differentiation make getting started simple and can save you time, skipping stages of the hPSC workflow while allowing you to invest in the time points most critical for your company’s process development.

There are multiple options for generating or sourcing these neural cell models:

• Starting from hPSCs: choose high-quality human induced pluripotent stem cell (iPSC) lines like SCTi003-A (female) and SCTi004-A (male) for optimal performance and reproducibility.
• Starting from Neural Progenitor Cells (NPCs): use a highly characterized neural progenitor intermediate like Human iPSC-Derived Neural Progenitor Cells for a confident start to your neural workflow.
• Starting from Forebrain Neuron Precursor Cells: jump right into experimentation with a highly pure population of Human iPSC-Derived Forebrain Neuron Precursor Cells, which express characteristic neuronal markers (Figure 6).
• Starting from Pre-Formed Neural Organoids: for a 3D model, choose Human iPSC-Derived Midbrain Organoids and culture these with STEMdiff™ Neural Organoid Maintenance Kit for optimal performance. Human iPSC-Derived Midbrain Organoids exhibit treatment-dependent neuronal activity for use in your drug discovery workflows (Figure 7).

For more information about STEMCELL’s neural portfolio and educational resources, or if you would like to learn more about how we can support your neuroscience research, please contact us at techsupport@stemcell.com.

References

1. Sun D et al. (2022) Why 90% of clinical drug development fails and how to improve it? Acta Pharm Sin B 12(7):3049 – 62.
2. Sequiera GL et al. (2022) Development of iPSC-based clinical trial selection platform for patients with ultrarare diseases. Sci Adv 8(14):eabl4370.
3. Wang Q et al. (2022) Assessment of a 3D neural spheroid model to detect pharmaceutical-induced neurotoxicity. ALTEX 39(4)560 – 82.
4. Chew LH et al. (2024) Methods to extract and analyze fluid from human pluripotent stem cell-derived choroid plexus organoids. Front Mol Neurosci 16:1243499.
5. D’Amour KA et al. (2005) Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat Biotech 23(12):1534 – 41.
6. Kattman SJ et al. (2011) Stage-specific optimization of activin/nodal and bmp signaling promotes cardiac differentiation of mouse and human pluripotent stem cell lines. Cell Stem Cell 8(2): 228 – 40.
7. Bardy C et al. (2015) Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro. PNAS 112(20):E2725 – E2734.