Pei-Ru Jhuang Ph.D.(c) & Tzu-Tang Wei Ph.D.
Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan

Introduction

Induced pluripotent stem cells (iPSCs) were first generated from mouse cells in 2006 and human cells in 2007 by reprogramming differentiated somatic cells back to a pluripotent state [1, 2]. Because iPSCs can proliferate extensively and differentiate into many specialized cell types, they offer a potentially renewable source of cells for research and clinical manufacturing [3]. Their clinical translation now includes direct cell transplantation, standardized production of blood or immune cells, and the use of patient-derived disease models to guide drug trials [3, 4]. The central question is therefore no longer whether iPSC-derived cells can be administered to patients, but whether they can provide durable and clinically meaningful benefits with acceptable long-term risks [3, 5].

Ophthalmology was the first field to enter human studies, partly because cells can be delivered locally and monitored directly by imaging [3]. In 2014, a Japanese team transplanted an autologous iPSC-derived retinal pigment epithelium sheet into a patient with neovascular age-related macular degeneration; no serious transplant-related adverse events were observed, although vision remained stable rather than clearly improving [6]. Later studies evaluated HLA-matched allogeneic retinal pigment epithelial cells, retinal organoid sheets for retinitis pigmentosa, and corneal epithelial sheets for limbal stem-cell deficiency. These small studies generally supported short-term safety and graft survival, but their sample sizes and uncontrolled designs were insufficient to establish visual efficacy [7-9]. A US phase I/IIa study is now evaluating autologous iPSC-derived retinal pigment epithelial cells for geographic atrophy associated with age-related macular degeneration [10].

The nervous system has become another major area of development. In a Japanese phase I/II study, seven patients with Parkinson’s disease received bilateral transplantation of allogeneic iPSC-derived dopaminergic progenitors and were followed for 24 months. No serious adverse events or tumorigenic overgrowth were reported, while motor examinations and brain imaging showed encouraging signals in some participants. Patient-reported and daily-function outcomes did not improve consistently, and the open-label, uncontrolled design prevents a definitive conclusion about efficacy [11].

In March 2026, Japan granted conditional and time-limited approval to AMCHEPRY (raguneprocel), the dopaminergic progenitor product used for Parkinson’s disease. It became the first iPSC-derived regenerative medicine product to receive marketing authorization, but post-marketing clinical study and surveillance remain necessary to obtain full approval [12]. Autologous iPSC-derived dopamine neurons are also being evaluated in a small US phase I study, while a separate US study is assessing the allogeneic CT1-DAP001 product [13, 14]. Japan also completed a four-patient clinical study of iPSC-derived neural stem/progenitor cells for subacute spinal cord injury. All four patients completed one year of follow-up, and no serious adverse events causally related to the therapy were reported; efficacy findings remain preliminary [15, 16]. Japan also conditionally approved RiHEART, an allogeneic iPSC-derived cardiomyocyte-sheet product for severe ischemic heart failure, in March 2026 [17].

Its supporting clinical study included eight patients without a concurrent control group, so post-marketing research must determine the durability of benefit and the contribution of surgery, immunosuppression and patient selection [18]. The simultaneous approvals of AMCHEPRY and RiHEART represented a regulatory milestone, but they were granted through Japan’s conditional regenerative-medicine pathway rather than conventional large confirmatory randomized trials [12, 17].

Clinical development has expanded beyond the eye, brain and heart. In 2024, investigators reported that the first participant receiving autologous chemically induced pluripotent stem-cell-derived islets for type 1 diabetes became insulin independent from day 75 and maintained near-normal glycemic control at one year. This was an important demonstration of biological function, but it remained a single-patient report, and the participant was already receiving immunosuppression following a previous liver transplant [19]. In the iPLAT1 study, autologous iPSC-derived platelets were administered to one patient with platelet-transfusion refractoriness; the primary safety objective was met, but no clear post-transfusion platelet-count increase was demonstrated [20].

iPSCs are also being developed as renewable manufacturing platforms. CYP-001, an allogeneic iPSC-derived mesenchymal stromal-cell product, initially showed manageable safety and an encouraging response rate in a 15-patient phase I study of steroid-resistant acute graft-versus-host disease [21, 22]. However, a subsequent randomized, placebo-controlled phase II study involving 65 patients did not meet its primary efficacy endpoint in 2026 [23]. This result illustrates why encouraging signals from small uncontrolled studies must be confirmed in comparative trials [5, 23].

FT516, an off-the-shelf engineered iPSC-derived natural killer-cell product, was evaluated with an anti-CD20 antibody and interleukin-2 in 55 patients with relapsed or refractory B-cell lymphoma. No dose-limiting toxicity was reported and the objective response rate was 58%, although the uncontrolled combination-therapy design did not isolate the contribution of FT516 [24]. FT819, an off-the-shelf iPSC-derived CD19 CAR-T-cell product, is currently being evaluated in systemic lupus erythematosus and other B-cell-mediated autoimmune diseases [25]. These programs demonstrate the potential use of iPSCs as standardized manufacturing platforms for immune-cell medicines [24, 25].

iPSCs can also influence clinical trials without being transplanted. Patient-derived iPSC motor neurons were used to identify ropinirole as a candidate treatment for amyotrophic lateral sclerosis. In a subsequent 20-participant phase I/IIa trial, adverse events were similar between ropinirole and placebo, but decline in the principal functional scale was not significantly different during the double-blind period [4].

Table 1. Current Clinical Progress of iPSC-Based Therapies

The study showed that iPSC models can generate therapeutic hypotheses and potential biomarkers but cannot replace adequately powered clinical endpoints [4, 5]. Current evidence shows that diverse iPSC-derived products can be manufactured and administered through multiple routes, and reported early cohorts have not identified a recurring pattern of graft-derived tumors [3]. Nevertheless, most trials remain small and focused primarily on safety, while long-term tumor risk, durability, batch consistency and comparative effectiveness remain unresolved [3, 5]. By 2026, iPSC medicine has progressed from demonstrating technical feasibility to determining whether well-characterized products can deliver reproducible and clinically meaningful benefit in larger controlled studies [3, 12, 17].

References

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