iPSC Cell Therapy Evolves Beyond Personalized Medicine Toward Universal Donor Approaches

Induced pluripotent stem cells (iPSCs) are adult cells reprogrammed into an embryo-like state. They have gone from a 2006 discovery to approved therapies in about two decades. This review by Wang, Zhang, Deng, and Gu traces two parallel strategies, autologous (a patient's own cells) and allogeneic (donor cells). It explains why treatments for age-related conditions such as macular degeneration, Parkinson's disease, and heart failure are now reaching patients.

The first decade focused on safety. Reprogramming moved from integrating viral vectors, which risked insertional mutagenesis and tumors, to non-integrating methods: episomal plasmids, Sendai virus, and modified mRNA. Differentiation also had to produce pure, mature cells without residual undifferentiated cells that could form teratomas. Retinal pigment epithelium (RPE), a simple monolayer, was the easiest first target. In September 2014, a 1.3 × 3.0 mm autologous iPSC-RPE sheet was transplanted into a patient with wet age-related macular degeneration, with stable vision and no immunosuppression.

The second patient exposed the real bottleneck. In 2015, whole-genome sequencing found copy number alterations, including one affecting a known oncogene, in the iPSCs and RPE that were absent from the original cells. The risk was probably low, but no framework existed for a release decision, so the program was suspended. Each autologous product took about a year and roughly 100 million yen (about US$1 million). Kyoto University's CiRA HLA-haplobank offered an alternative. Its first three lines matched about 32% of the Japanese population, rising to about 40% by 2022. Haplobank RPE preparation took about one month at under 20 million yen (about US$200,000).

Genome editing and better differentiation accelerated allogeneic work. In 2019, iPSCs lacking B2M and CIITA and overexpressing CD47 evaded immune attack in immunocompetent recipients. Sana Biotechnology's first-in-human UP421 study showed edited primary islet cells making glucose-responsive C-peptide for 12 weeks without immunosuppression, although only a marginal cell mass was given. In a phase 1/2 Parkinson's trial of seven patients, four of six evaluable patients improved motor function, with no tumors. Japan granted conditional, time-limited approval to AMCHEPRY/raguneprocel on March 6, 2026, alongside Cuorips' RiHEART cardiomyocyte sheets for severe heart failure.

Chemical reprogramming is reviving the autologous route. Small-molecule cocktails, first shown in mouse cells in 2013 and extended to human cells in 2022, avoid exogenous genetic material and are chemically defined and scalable. Starting materials now include adipose stromal cells, fibroblasts, blood cells, and select T cell subsets. Cross-laboratory reproducibility has not been formally benchmarked, and head-to-head comparisons with transcription factor methods are limited.

The authors conclude the two pathways serve different needs. Allogeneic products suit rapid, consistent, broadly distributed treatment. Autologous products may suit chronic diseases needing durable engraftment. HLA-bank coverage depends on population genetics, and diverse populations need many more lines. Matching also leaves minor histocompatibility differences, so most allogeneic programs still use short-course immunosuppression.