iPSCs in Drug Development: Disease Modeling and Screening

Many CNS drug development programs encounter a common challenge. The molecule is designed against a human sequence or a human receptor, but the cells it must reach sit inside a living brain. Historically, access to scalable, disease-relevant human neuronal models was limited, making it difficult to investigate certain human-specific mechanisms during early drug development. They used animal neurons, tumor-derived cell lines, or scarce post-mortem tissue, and hoped the results would translate.

Since the discovery of induced pluripotent stem cells (iPSCs) in 2006, researchers have gained new ways to study human biology in accessible cellular systems. An ISSCR symposium held in Kyoto in October 2026 marked two decades of iPSC research ^[1]. Beyond these milestones, a practical question remains for drug developers: what can iPSCs tell us about a drug candidate before it reaches a patient?

The Discovery of Induced Pluripotent Stem Cells

The story began in 2006, when Kazutoshi Takahashi and Shinya Yamanaka showed that four transcription factors, Oct3/4, Sox2, Klf4 and c-Myc, could reprogram mouse fibroblasts into a pluripotent state. The cells behaved much like embryonic stem cells, but no embryo was needed ^[2].

The obvious next question was whether human cells would respond the same way. In 2007, they did. Yamanaka's group, and independently James Thomson's group, generated iPSCs from human somatic cells ^[2]. This opened the possibility of generating patient-specific cell models from accessible somatic cells.

The significance was recognized quickly. In 2012, Yamanaka shared the Nobel Prize in Physiology or Medicine with John Gurdon for showing that mature cells can be reprogrammed to pluripotency ^[3]. Since then, the field has followed three paths, each building on the last.

Figure 1. Landmark publications on the mechanisms of reprogramming and the medical applications of iPSCs and related technologies ^[2].

iPSC-Derived Cell Therapies: From Early Transplants to Conditional Approvals

The earliest ambition was regenerative medicine. If disease destroys a specific cell type, perhaps iPSC-derived cells could replace it.

Clinical transplantation began in 2014, while the first conditional product approvals followed in Japan in 2026 ^[4]. Japan granted conditional, time-limited approval to the first iPSC-derived products: AMCHEPRY® (raguneprocel) from Sumitomo Pharma and Racthera, which delivers dopaminergic neural progenitors for Parkinson's disease, and Cuorips' RiHEART®, a cardiomyocyte sheet for severe ischemic heart failure ^[5-6]. These approvals represent important clinical milestones, although longer-term effectiveness and safety remain subject to further evaluation and post-marketing evidence collection. Longer-term efficacy data are still to come, and new ideas keep arriving, such as engineered iPSC-derived macrophages presented at ESGCT 2026 as a possible approach to amyloid pathology ^[7].

Yet making cells good enough to transplant forced the field to solve a broader problem: how to produce defined human cell types reliably. That capability opened the second path.

iPSC Disease Modeling: Patient-Derived Cells, Isogenic Controls and Organoids

If a neuron can be made from a patient's skin cell, it carries that patient's genome. Disease-causing variants and their surrounding genetic background come along automatically. For the first time, researchers could watch disease biology unfold in the human cell type where it happens.

Gene editing has sharpened this approach. By introducing a mutation into a healthy line or correcting it in a patient line, researchers can create isogenic pairs to study a specific variant within a shared genetic background. This reduces confounding from donor-to-donor variation and helps clarify the variant’s contribution to observed phenotypes, although independent clones, differentiation variability, and potential unintended changes must still be considered. Organoids have taken the idea into three dimensions; in Kyoto, speakers presented islet organoids, gene-edited brain organoids for epilepsy-related mutations and alveolar organoids for infection research ^[1].

Cyagen's iPSC platform is built on the same principle: well-characterized lines, defined differentiation protocols and engineered disease variants compared against matched controls. Once disease can be modeled in human cells, the next step follows naturally: testing drugs against it.

Figure 2. Service process of iPSC reprogramming.

How iPSC-Derived Cells Support Drug Screening and Development

Beyond regenerative medicine, iPSC-derived cells are also being investigated as engineered cellular immunotherapies. For example, Fate Therapeutics’ investigational iPSC-derived CD19 CAR-T product FT819 has generated preliminary clinical data in autoimmune disease ^[8].

Figure 3. The structure of FT819 ^[9].

Alongside their potential as therapies, iPSC-derived cells serve as test systems for evaluating other drugs. They help researchers examine whether a candidate works as intended in the relevant human cell type. This is particularly useful for sequence-specific drugs such as ASOs and siRNAs, and for antibodies whose targets or uptake receptors differ between species.

The value of these assays depends on reliable characterization and a clearly defined research question. In the regulatory setting, the FDA’s March 2026 draft guidance on new approach methodologies (NAMs) emphasizes a defined context of use, human biological relevance, technical characterization and fit-for-purpose performance ^[10]. The draft provides a framework for considering NAMs in regulatory submissions, rather than a prescription for building research platforms.

iPSC-Derived Cortical Neurons for CNS Drug Development

Back to the wall we started with: the blood-brain barrier. For CNS drug development, crossing the blood–brain barrier and achieving productive delivery to target cells are distinct challenges. While iPSC-derived neurons cannot independently assess blood–brain barrier transport, they provide a human cellular system for investigating neuronal uptake, intracellular activity, and target-specific pharmacodynamic responses.

For antibody-based and oligonucleotide therapeutics, these studies can help characterize selected aspects of cellular delivery and biological activity before candidates advance to more complex preclinical models. For programs targeting neurons, the key question remains: can the molecule enter human neurons and produce the intended biological effect?

To answer this question, we first characterized the identity and function of the differentiated neurons. The cultures expressed the neuronal markers NeuN and MAP2, while patch-clamp recordings demonstrated sodium and potassium currents and action potential firing. Flow cytometry also detected transferrin receptor (TfR) and CD98 expression, two receptors being explored for brain shuttle delivery of biologics.

Figure 4. Characterization of human iPSC-derived cortical neurons.

(A) Immunofluorescence staining for NeuN and MAP2, with DAPI nuclear counterstaining. (B) Patch-clamp recordings showing voltage-gated sodium and potassium currents, evoked action potentials, and spontaneous action potentials. (C) Flow cytometric analysis of TfR, CD98 and IGF1R expression.

Next, we asked whether the system could support the study of Alzheimer’s disease-associated changes. Cortical neuron cultures carrying the APP Swedish mutation (APPswe) showed elevated levels of Aβ40, Aβ42, p-Tau181, and p-Tau217 in the culture supernatant compared with wild-type controls.

Figure 5. AD-associated biomarkers in APPswe cortical neuron culture supernatants.

(A) Aβ40 and Aβ42 levels and (B) p-Tau181 and p-Tau217 levels in culture supernatants from APPswe and wild-type cortical neurons. APPswe cultures showed elevated levels of all four markers, supporting the use of this system to study selected AD-associated biochemical changes.

With a functional, disease-relevant system in place, we turned to drugs. ASOs added directly to the culture medium, without transfection reagents, produced a dose-dependent reduction in target gene expression under the tested conditions. This free-uptake approach allows researchers to evaluate oligonucleotide activity without artificial transfection-assisted delivery, but it does not reproduce the pharmacokinetics, tissue distribution or cellular exposure conditions associated with intrathecal administration.

Figure 6. ASO-mediated gene knockdown through free uptake.

Target gene expression in iPSC-derived cortical neurons after 7 and 14 days of ASO exposure at two dose levels, without transfection reagents. Expression was normalized to GAPDH. Higher-dose treatment produced greater knockdown at both time points.

Our newest data extend this to both delivery routes discussed above. Together, they show that one human neuron system can test whether a TfR-binding antibody is internalized by neurons and whether different oligonucleotide modalities engage their target.

Figure 7. TfR-binding antibody uptake and siRNA-mediated gene silencing in human cortical neurons.

(A) Time-dependent cell-associated fluorescence following TfR antibody treatment. (B) Target mRNA expression at 24 and 72 hours following RNAiMAX-mediated siRNA transfection. (C) Target mRNA expression after 3, 7, and 14 days of free uptake of lipid-modified siRNA at the indicated concentrations.

Connecting Human Cellular Models with In Vivo Evidence

Human neurons in a dish answer cell-level questions well, but they cannot answer everything. They do not model blood-brain barrier crossing, systemic pharmacokinetics, distribution across brain regions or toxicity in other organs. iPSC-derived neurons are often less mature than adult neurons, and lines can drift genetically in culture, which is why characterization and matched controls belong in every experiment.

The practical answer is not to choose between cells and animals, but to sequence them:

1. Screen candidates in iPSC-derived human neurons to confirm target engagement on the human sequence.
2. Use isogenic disease lines to check that knockdown or binding changes a disease-relevant readout.
3. Move the best candidates into appropriate in vivo models to test delivery, tissue exposure, pharmacodynamics, and disease-relevant outcomes. Humanized mouse models may be particularly useful when species-specific differences limit target engagement or biological relevance.
4. Feed in vivo results back into the cell assay to refine potency thresholds for the next round.

In this workflow, iPSC-derived neurons complement in vivo studies. They make each one more informative, because fewer candidates arrive untested in the human cells they are meant to reach.

Twenty years after the discovery of iPSCs, researchers can investigate selected aspects of human disease biology and therapeutic responses in experimentally accessible human cell systems.

For CNS drug development, iPSC-derived neurons can support the characterization of neuronal identity and function, cellular uptake, target modulation, and disease-relevant readouts. These approaches complement, rather than replace, appropriately selected in vivo models needed to evaluate tissue exposure, pharmacodynamics, and broader physiological responses.

By combining iPSC-based research platforms with genetically engineered mouse models and preclinical research services, Cyagen supports the generation of complementary evidence to inform therapeutic candidate evaluation.

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References

[1] Kilbourne K. Global stem cell research community gathers in Kyoto, Japan to celebrate 20 years of iPSC discovery and innovation [Internet]. International Society for Stem Cell Research; 2026 Oct 19 [cited 2026 Oct 29].

[2] Yamanaka S. Two decades of induced pluripotent stem cell research: From discovery to diverse applications. Cell Stem Cell. 2026 Mar 5;33(3):372-381. doi: 10.1016/j.stem.2026.02.003. PMID: 41795426.

[3] Nobel Prize Outreach. The Nobel Prize in Physiology or Medicine 2012 [Internet]. NobelPrize.org; [cited 2026 Oct 29].

[4] Mandai M, Watanabe A, Kurimoto Y, Hirami Y, Morinaga C, Daimon T, Fujihara M, Akimaru H, Sakai N, Shibata Y, Terada M, Nomiya Y, Tanishima S, Nakamura M, Kamao H, Sugita S, Onishi A, Ito T, Fujita K, Kawamata S, Go MJ, Shinohara C, Hata KI, Sawada M, Yamamoto M, Ohta S, Ohara Y, Yoshida K, Kuwahara J, Kitano Y, Amano N, Umekage M, Kitaoka F, Tanaka A, Okada C, Takasu N, Ogawa S, Yamanaka S, Takahashi M. Autologous Induced Stem-Cell-Derived Retinal Cells for Macular Degeneration. N Engl J Med. 2017 Mar 16;376(11):1038-1046. doi: 10.1056/NEJMoa1608368. PMID: 28296613.

[5] Sumitomo Pharma Co., Ltd., RACTHERA Co., Ltd. Announcement on the approval for manufacturing and marketing authorization of the allogeneic iPS cell-derived dopaminergic neural progenitor cell product “AMCHEPRY” in Japan [Internet]. 2026 Mar 6 [cited 2026 Oct 29].

[6] Cuorips Inc. World’s first iPSC-derived cardiomyocyte therapy for heart failure receives conditional approval in Japan [Internet]. 2026 Mar 6 [cited 2026 Oct 29].

[7] Felde M. Cell-based therapy for amyloid pathology in Alzheimer's disease using engineered iPSC-Macs [conference presentation]. ESGCT 33rd Annual Congress; 2026 Oct 27–30; Hamburg, Germany. Oral presentation OR011.

[8] Fate Therapeutics, Inc. Fate Therapeutics presents updated preliminary data for FT819 in active lupus nephritis at American Society of Nephrology Kidney Week 2026 [Internet]. 2026 Oct 26 [cited 2026 Oct 29].

[9] Fate Therapeutics, Inc. FT819 [Internet]. [cited 2026 Oct 29].

[10] U.S. Food and Drug Administration. General considerations for the use of new approach methodologies in drug development: draft guidance for industry [Internet]. Silver Spring (MD): FDA; 2026 Mar [cited 2026 Oct 29].