Ophthalmic applications of iPSCs have progressed significantly, with particular emphasis on retinal disorders such as age-related macular degeneration (AMD) (Tsai et al., 2015; Fields et al., 2016). iPSCs can be differentiated into retinal pigment epithelium (RPE) cells and photoreceptors, 2 cell types that are critical for normal visual function (Garcia et al., 2015; Hazim et al., 2017; Dehghan et al., 2022). In AMD, loss of RPE cells disrupts photoreceptor function and leads to vision loss (De et al., 2007; Zhang et al., 2021). Preclinical studies indicate that subretinal delivery of iPSC-derived RPE cells can protect or restore retinal function (Tokuyama et al., 2021).

Clinical translation has already begun. In Japan, autologous iPSC-derived RPE cells were transplanted into a patient with exudative AMD, and the graft remained stable without major complications (Mandai et al., 2017). More recently, Soma et al. (2024) showed that iPSC-derived corneal epithelium could also be engrafted safely in humans (Soma et al., 2024).

Donor-derived iPSCs are being investigated as an allogeneic, “off-the-shelf” source of RPE cells, while photoreceptor replacement is under investigation for advanced retinal disease (Maeda and Takahashi, 2023).

For instance, transplanted human iPSC-derived photoreceptors, when placed into cone-dominant ground squirrels, survived for 4 months but exhibited poor integration and no functional recovery (Yu et al., 2024). In Pde6b knockout rats, grafts survived longer, maintained visual responses, and showed no abnormal growth (Yang et al., 2021). Zhao et al. (2024) used chemically induced pluripotent stem cells (CiPSCs) in mice and achieved retinal integration and some functional rescue (Zhao et al., 2024).

Ensuring long-term safety is still a central challenge. GMP-grade iPSC-derived RPE cells did not form tumors in immunodeficient rodents, but abnormal proliferation is still possible (Zhang et al., 2021). CRISPR-modified MHC-II-deficient RPE cells survived in non-human primates without signs of inflammation (Ishida et al., 2024). Other editing strategies are being developed to remove oncogenic sequences and improve safety (Martin et al., 2020).

Clinical trials are now testing whether iPSC-derived RPE and photoreceptor grafts can provide lasting functional recovery in AMD and other retinal diseases (Liu et al., 2024).

Beyond ophthalmology, patient-derived iPSCs are increasingly applied to model neurodegenerative diseases such as Parkinson’s disease and ALS (Soldner et al., 2009; Fujimori et al., 2018). These models enable the study of disease mechanisms in a patient-specific setting and provide platforms for testing therapeutic strategies. Neurons generated from patient iPSCs have been used to reproduce disease phenotypes in vitro and to evaluate candidate interventions (Antoniou et al., 2022).

Parkinson’s disease has received particular attention. This disorder is defined by the progressive loss of dopaminergic neurons in the substantia nigra, which results in motor decline. Patient-derived iPSCs can be differentiated into dopaminergic neurons. These cells allow researchers to investigate disease mechanisms and explore cell replacement therapies (Doi et al., 2020). In preclinical models, transplantation of these neurons has restored dopamine levels and improved motor symptoms (Song et al., 2020; Morizane, 2023). Building on these findings, clinical studies are ongoing to examine the safety and potential efficacy of iPSC-based therapies in patients (Sugai et al., 2021). One notable case report described clinical improvement within 18–24 months following autologous transplantation of iPSC-derived dopaminergic progenitors (Schweitzer et al., 2020).

iPSC technology has enabled large-scale production of immune cells, opening new avenues for cancer immunotherapy (Zhou et al., 2022). NK cells derived from iPSCs are particularly valuable because they can eliminate malignant cells without prior sensitization. When engineered with chimeric antigen receptors (CARs), these NK cells acquire enhanced specificity and cytotoxicity toward tumor cells (Li et al., 2018). A prominent example is FT596, an allogeneic CAR-NK product generated from iPSCs, which has advanced into clinical trials in the United States. This therapy incorporates an anti-CD19 CAR to improve the persistence and activity of NK cells in vivo (Ghobadi et al., 2025).

iPSC-derived T cells are also under investigation for adoptive immunotherapy. These cells can be engineered to carry tumor-specific receptors, enabling selective targeting of cancer cells (Themeli et al., 2013). Studies have demonstrated that iPSC-derived T cells display strong anti-tumor activity and sustained survival in vivo (Kawamoto et al., 2021; Cichocki et al., 2023). More recently, a feeder-free approach that inhibits G9a/GLP histone methyltransferases has been developed, yielding populations that closely resemble mature αβ T cells (Jing et al., 2024).

In addition, dendritic cells (DCs) generated from iPSCs are being explored for cancer vaccination. By loading these DCs with tumor antigens, they can be used to prime the immune system against specific malignancies (Mellman and Steinman, 2001; Calmeiro et al., 2020; Oba et al., 2021). Preclinical studies have shown that iPSC-derived DCs can trigger robust tumor-specific immune responses, demonstrating their potential as personalized immunotherapy strategy (Ackermann et al., 2020; Calmeiro et al., 2020; Oba et al., 2021).

Despite these advances, translation of iPSC-derived immune cells into the clinic continues to face challenges, including genomic instability, the potential for tumor formation, and variability in differentiation outcomes (Madrid et al., 2024). Addressing these concerns requires refinement of reprogramming and differentiation methods alongside the introduction of strict quality control standards to ensure clinical safety (Utikal et al., 2009; He et al., 2023). Ongoing efforts aim to resolve these limitations and advance their clinical use (Fang et al., 2025).

iPSC-derived cardiomyocytes are being investigated for cardiac repair (Kawamura et al., 2023). Shiba et al. (2016) were among the first to show that transplanting iPSC-derived cardiomyocyte patches into primates could support myocardial regeneration, although transient arrhythmias were noted in some animals (Shiba et al., 2016).

Miyagawa et al. (2022) later used clinical-grade, HLA-homozygous hiPSC-derived cardiomyocytes in a porcine model and observed improved cardiac function and angiogenesis, with no evidence of tumors, genetic abnormalities, or arrhythmias. A study by Jebran et al. (2025) involved transplanting engineered heart muscle composed of iPSC-derived cardiomyocytes and stromal cells into rhesus macaques with chronic heart failure. The grafts improved contractility and remained stable for several months, without evidence of arrhythmias or tumor formation. These findings supported a first-in-human implantation, which demonstrated graft survival and structural remuscularization in a patient with advanced heart failure (Jebran et al., 2025).

Early clinical trials have now begun evaluating cardiomyocyte sheets in patients (Kawamura et al., 2023). In one case, a patient with ischemic cardiomyopathy received an iPSC-derived cardiomyocyte patch and showed improved cardiac function 6 months after surgery, with no major complications (Miyagawa et al., 2022). Still, several challenges remain, particularly achieving long-term cell survival, stable electrical integration, and scalable, consistent production. Current efforts aim to improve cell maturation, reduce arrhythmogenic risk, and refine GMP-compliant manufacturing protocols (Silver et al., 2021; Jiang et al., 2024; Raniga et al., 2024).

An overview of clinical trials involving iPSC-based therapies across multiple indications is provided in Table 1.

In the United States, the FDA regulates most iPSC-derived products as 351 HCT/Ps under the Public Health Service Act when they are more than minimally manipulated or used for non-homologous purposes (U.S. Food and Drug Administration, 2020). These products are classified as biologics and require an Investigational New Drug (IND) application before clinical use (U.S. Food and Drug Administration, 2007). While early-stage trials do not require a separate manufacturing license, detailed chemistry, manufacturing, and control (CMC) information is essential. The FDA supports accelerated approval through programs like The RMAT designation applies to therapies intended for serious conditions and includes requirements for post-marketing safety measures, such as Risk Evaluation and Mitigation Strategies (REMS) (Hirai et al., 2023).

In the European Union (EU), iPSC-based therapies are regulated by the EMA as Advanced Therapy Medicinal Products (ATMPs) under Regulation EC No. 1394/2007. Their approval must go through the centralized procedure, and clinical trials require authorization under the Clinical Trials Regulation (CTR 536/2014) (Madrid et al., 2024).

EMA guidelines enforce ATMP-specific Good Manufacturing Practices (GMP) and require extensive data on tumorigenicity, immunogenicity, and long-term safety. Ethical standards are strict, with bans on the use of embryonic material and mandatory informed donor consent. Post-marketing safety is tracked through Risk Management Plans (RMPs) and EudraVigilance (Martins and Ribeiro, 2025).

Japan follows a hybrid regulatory approach through the Pharmaceuticals and Medical Devices Agency (PMDA). iPSC therapies fall under the PMD Act and the Act on the Safety of Regenerative Medicine (ASRM). Japan allows clinical trials to begin through prior notification, which streamlines early-phase studies (Azuma and Yamanaka, 2016). A unique feature is the conditional and time-limited approval system, which permits product use before full efficacy data is available, with extended post-marketing monitoring for up to 7 years (Song S. J. et al., 2024). Japan also limits clinical germline editing for reproductive purposes while permitting it for research purposes (Ishii, 2015; Ishii, 2017).

While each agency has its own priorities, all three participate in ongoing Although regulatory agencies differ in focus, they are involved in joint efforts to align standards. Examples include the FDA–EMA Parallel Scientific Advice (PSA) program and collaboration through the International Council for Harmonisation (ICH) (Thor et al., 2023).

The IND (FDA) and IMPD (EMA) submission formats share core requirements but differ in implementation. Both require comprehensive documentation on the cell source, reprogramming and differentiation protocols, and assays for identity, purity, and potency (Hirai et al., 2023). In the EU, clinical-grade manufacturing facilities must already be GMP-certified at the trial stage, while in the U.S., quality oversight is integrated into the IND process without a separate facility license (Hirai et al., 2023). Post-trial safety planning also differs: the U.S. uses REMS, while the EU mandates an RMP (Hirai et al., 2023). Japan follows similar technical requirements but allows earlier trial entry via simplified notification-based submissions (Anklam et al., 2022; Hirai et al., 2023; Su et al., 2024).

Figure 3 illustrates how these regulatory differences guide the selection of reprogramming methods based on clinical application, safety, efficiency, and scalability.

Regulatory standards for iPSC therapy manufacturing are still developing and vary between regions. In Europe, particular emphasis is placed on aseptic processing, batch-to-batch consistency, and complete traceability, especially important due to the absence of terminal sterilization option (Martins and Ribeiro, 2025). The FDA places growing emphasis on in-process controls, raw material standards, and comparability between manufacturing runs, particularly in xeno-free, feeder-free systems (Anklam et al., 2022; Hirai et al., 2023). Japan’s regulatory framework is guided by a risk-based philosophy, placing strong importance on tracking the full history of each cell line, confirming the reliability of master cell banks, and monitoring essential quality features throughout production (Azuma and Yamanaka, 2016). Though the specifics vary by region, the overarching focus remains the same: producing safe, consistent therapies and preventing tumor-related risks.

A number of early clinical trials show how iPSC-based therapies are starting to enter real-world treatment pathways. In Japan, the Kyoto Trial involved transplanting iPSC-derived dopaminergic progenitors from healthy donors into Parkinson’s patients. Approved conditionally by the PMDA, the trial showed improved motor function with no evidence of tumor formation (Sawamoto et al., 2025; Takahashi et al., 2025). In a similar effort, the RIKEN trial used autologous iPSC-derived RPE sheets to treat macular degeneration, reporting no serious side effects during long-term follow-up (Mandai et al., 2017).

In the U.S., Fate Therapeutics received IND clearance and RMAT designation for iPSC-derived NK (FT500) and CAR-T (FT819) therapies, supporting early entry into trials for solid tumors and autoimmune disease (Fate Therapeutics, 2019; Hong et al., 2020; Fate Therapeutics, 2025). Gameto’s Fertilo, an iPSC-derived ovarian support cell therapy, became the first iPSC product to enter Phase III trials in the U.S. (Bruna et al., 2025).

In Europe, while no iPSC-based product has received full marketing approval, several trials are progressing under EMA oversight (Song S. J. et al., 2024). EBiSC and HipSci provide GMP-grade iPSC lines under defined protocols (Kim et al., 2019; Mah et al., 2023). In 2025, OpCT-001, an iPSC-derived photoreceptor therapy for retinal disease, received Fast Track status from the FDA (HPSC, 2024). Additionally, XellSmart Biomedical launched iPSC-based neural progenitor trials for ALS and Parkinson’s disease in both the U.S. and Asia following FDA IND clearance (Svendsen and Svendsen, 2024; XellSmart Biomedical Co, 2025).

Although no ICH guideline is specific to iPSC therapies, regulators apply modified versions of existing frameworks, including ICH Q5D (cell substrates), S6 (R1) (preclinical safety), E6 (R2) (Good Clinical Practice), and Q12 (product lifecycle management) (MC, 2023; Soares and Ribeiro, 2024). Interpretation and implementation vary by region, contributing to differences in safety and quality expectations (Hirai et al., 2023; Selfa Aspiroz et al., 2025).

Several international organizations, including ISSCR, ISCT, and GAiT, are working to define standardized criteria for assessing potency, tumor risk, and genomic integrity in iPSC-based products (Sullivan et al., 2020; Turner, 2021; Song H. W. et al., 2024). Tools like gastruloids are also being evaluated for use in reproductive toxicity testing under ICH S5 (R3) (S, 2021). Japan’s alignment with ICH principles and participation in regulatory dialogues is further accelerating convergence (N., 2003; Medical, 2025). As more clinical data becomes available, dedicated ICH guidance for iPSC-based products is expected to emerge, supporting safer and more streamlined global development.

Autologous approaches involve reprogramming a patient’s own somatic cells into iPSCs, followed by differentiation into the required cell type for transplantation (Scheiner et al., 2014; Mandai et al., 2017; Sugimoto et al., 2022) (Figure 4A). A key advantage is immune compatibility: since the cells originate from the patient, they are unlikely to be rejected and do not cause graft-versus-host disease (GvHD) (Morizane et al., 2013). Long-term immunosuppression is generally not needed (Cerneckis et al., 2024).

Parkinson’s disease is among the most studied targets for autologous iPSC-based therapy. Patient-derived dopaminergic neurons are being developed to replace lost cells and restore motor function (Hallett et al., 2015). While this approach reduces immune risk, it is time-consuming and technically demanding (Morizane et al., 2013; Madrid et al., 2021). The time required for reprogramming and differentiation, often several months, makes autologous iPSC therapies unsuitable for acute conditions like stroke or myocardial infarction (Fujimori et al., 2017; Madrid et al., 2021; Yan et al., 2024). Because each product is patient-specific, the process is labour-intensive and expensive, and results can vary from one batch to another (Cha et al., 2023).

Genetic defects present in the patient’s cells may also carry over into the iPSC-derived cells, which could compromise the intended therapeutic effect (Liang et al., 2020; Wang et al., 2020; Cerneckis et al., 2024). In such cases, genetic screening and correction, when feasible, may be needed prior to transplantation (Madrid et al., 2021).

Allogeneic approaches rely on iPSC lines derived from healthy donors (McKenna and Perlingeiro, 2023) (Figure 4B). These cell lines can be expanded and banked in advance, allowing off-the-shelf use. A shared source also simplifies manufacturing and reduces production costs by eliminating the need to generate patient-specific lines.

A major limitation is immune compatibility. Since donor cells are not matched to the recipient, they may be recognized as foreign and rejected (Sasaki et al., 2015). To prevent this, patients typically require immunosuppressive therapy required (McKenna and Perlingeiro, 2023). Extended use increases the risk of infection and may lead to metabolic or cardiovascular side effects (McKenna and Perlingeiro, 2023).

One strategy to reduce rejection involves using iPSC lines from donors with common HLA haplotypes, allowing partial matching across broader patient groups. For example, a 100-line HLA-matched iPSC bank could cover an estimated 78% of European Americans, 52% of Hispanics, and 45% of African Americans (Garreta et al., 2018). Although this approach improves compatibility, short-term immunosuppression may still be required, particularly for transplants in immune-privileged sites such as the brain or eye (Taylor et al., 2012).

Figure 5 highlights key differences between autologous and allogeneic iPSC-based therapies and summarizes factors contributing to immune rejection in clinical settings.

Scaling iPSC production for clinical use remains difficult. Standard 2D cultures, though useful for research, are labor-intensive and poorly suited for consistent, large-scale manufacturing. As a result, there is growing interest in suspension-based cultures and bioreactors, which enable higher cell yields and offer greater control over growth conditions (Cuesta-Gomez et al., 2023; Yehya et al., 2024).

What makes this more challenging is the sensitivity of iPSCs to even small changes in culture conditions. Maintaining uniform pluripotency and genetic stability across large batches is difficult. Variants can emerge during expansion, some minor, others more significant, compromising both safety and function (Liang and Zhang, 2013; Andrews et al., 2017; Yang et al., 2024). The persistence of undifferentiated cells, unintended lineage specification, and chromosomal abnormalities can all increase the risk of tumor formation, making stringent quality control essential (Liang et al., 2013; Takei et al., 2020; Zhong et al., 2022).

Bioreactor and 3D suspension platforms have improved scalability and reduced batch-to-batch variation (Cuesta-Gomez et al., 2023). Still achieving uniform quality across various iPSC production systems remains challenging (Mamaeva et al., 2022). However, tools such as single-cell transcriptomics, live-cell imaging, and high-throughput screening have significantly advanced real-time tracking of differentiation processes and genomic stability (Huang et al., 2017; Wu et al., 2022; Nourreddine et al., 2024). Yet, no unified global criteria exist for what qualifies as a clinically acceptable iPSC product, an ongoing challenge for both regulatory alignment and broader clinical implementation (Song S. J. et al., 2024).

Alongside scale-up challenges, iPSC manufacturing for therapeutic use must also meet the specific GMP regulations set by each region. In the United States, the Food and Drug Administration (FDA) regulates iPSC-based therapies as human cells, tissues, and cellular and tissue-based products (HCT/Ps), under 21 CFR Parts 210, 211, and 1,271. This includes donor screening, validated processes, product testing, and submission of safety data before Investigational New Drug (IND) approval is granted (Jha et al., 2021).

In Europe, the EMA designates iPSC therapies as Advanced Therapy Medicinal Products (ATMPs), subject to centralized review, detailed traceability, and compliance with EU GMP guidelines, including Annexes 2 and 13 (De Sousa et al., 2017b).

Japan has adopted a more flexible framework. In 2014, the PMDA introduced a conditional, time-limited approval system that allows regenerative therapies, including iPSC-based products, to enter clinical use based on early-phase safety and efficacy data, with continued post-market surveillance (Sipp et al., 2018).

These regulatory differences not only affect the speed and cost of clinical translation but also complicate global standardization and equitable access to iPSC-based therapies.

Developing iPSC-based therapies is both time-consuming and expensive (Madrid et al., 2021; McKenna and Perlingeiro, 2023). The generation of a patient-specific iPSC line under Good Manufacturing Practice (GMP) conditions can take several months and cost more than $100,000 (Jha et al., 2021; Madrid et al., 2024). This estimated cost includes donor eligibility testing, reprogramming using non-integrating GMP-grade vectors, establishment of a master cell bank, and comprehensive release testing for sterility, identity, karyotypic stability, and pluripotency markers under current GMP standards (McKenna and Perlingeiro, 2023). It also accounts for documentation, facility overhead, and regulatory compliance.

In addition to these baseline expenses, the overall cost differs depending on the application. Autologous iPSC lines made for individual patients require custom production, which is more expensive than shared allogeneic lines. Drug screening and disease modeling are less demanding, since they do not require GMP conditions. In Japan, centralized production and access to HLA haplobanks help keep costs lower. In the United States and Europe, production is less centralized, and regulatory processes are more rigid. This, along with patient-specific workflows, makes manufacturing slower and more expensive (Jha et al., 2021; Madrid et al., 2024). This does not include the time and resources needed for differentiation and quality testing (McKenna and Perlingeiro, 2023). Autologous iPSC therapy is not suitable for acute conditions like stroke or myocardial infarction. Cost, infrastructure, and regulation remain obstacles to clinical use (Madrid et al., 2024).

A key ethical concern in iPSC-based therapy is how access will be handled. Generating clinical-grade lines is costly, technically demanding, and requires trained staff and facilities that are not available in all settings. These factors make it difficult to scale the technology in a way that benefits all patient populations equally, potentially worsening existing disparities in healthcare access (Zheng, 2016; Volarevic et al., 2018; Moradi et al., 2019).

Efforts are underway to address this gap. Efforts are underway to improve how iPSC-based therapies are produced at scale and to make manufacturing more cost-effective, with support from public and non-profit sectors (Huang et al., 2019).

Recent techno-economic studies suggest that automation and scalable manufacturing platforms could reduce labor costs and improve reproducibility, helping expand access in the long term (Nießing et al., 2021; Kuebler et al., 2023). At the same time, regulatory and policy discussions have focused on how to ensure fair access and avoid restricting these therapies to only those with financial or institutional advantage (Isasi and Knoppers, 2011).

For instance, the European Bank for induced pluripotent Stem Cells (EBiSC) is a non-profit repository that provides researchers with access to a wide range of iPSC lines, promoting equitable availability of these resources (De Sousa et al., 2017a; De Sousa et al., 2017b; Huang et al., 2019; Steeg et al., 2020; Mah et al., 2023).

Using human iPSCs in the clinic brings a number of ethical concerns to light, especially when it comes to informed consent, protecting personal genetic information, and ensuring treatments are fairly accessible. Although HLA-matched iPSC banks make allogeneic therapies more practical, they also demand careful handling of donor privacy and data protection. Donors must be fully informed not only about somatic cell reprogramming but also the potential long-term use, sharing, and modification of their iPSC lines in clinical and research settings (Lowenthal et al., 2012; McCaughey et al., 2016). The risk of reidentification from genomic data further underscores the importance of compliance with international privacy regulations such as GDPR and HIPAA.

Gene-editing tools like CRISPR-Cas9, while promising for correcting mutations in iPSCs, raise concerns about unintended edits, long-term effects, and misuse. Although iPSCs are not used for germline editing, the He Jiankui case, involving the birth of gene-edited children, highlighted the need for strict ethical oversight in clinical gene editing (Greely, 2019; Guo et al., 2023). Although iPSC editing is confined to somatic cells and considered reversible, it still employs the same tools used in germline modification, reinforcing the need for clear ethical limits (Greely, 2019; Guo et al., 2023).

It's still difficult to ensure that iPSC therapies are available to everyone, since making clinical-grade cells requires equipment and expertise that many places simply do not have (Zheng, 2016; Moradi et al., 2019). One way to close this gap is by supporting public biobanks and non-profit groups like EBiSC, which help make these therapies more fairly and widely accessible (De Sousa et al., 2017b; Mah et al., 2023).