In 2006, stem cell scientist Shinya Yamanaka was awarded the 2012 Nobel Prize in Physiology or Medicine for reprogramming adult cells into induced pluripotent stem cells (iPS cells). Based on this achievement, researchers across Japan are cultivating cells into retinal strips, myocardial slices, or neuronal clusters in order to treat blindness, repair the heart, and reverse neurodegenerative diseases. Early clinical trials suggest that these cells may indeed be useful for treating different conditions such as Parkinson's disease or spinal cord injury.

Now, after nearly two decades of arduous efforts and numerous setbacks, Japan hopes to bring these therapies to the market. According to the journal Nature, there are over 60 ongoing clinical trials of iPS cells worldwide, with nearly one-third conducted in Japan.

Clinical breakthrough in eye diseases

In 2014, ophthalmologist Masahiro Takahashi from Kobe Eye Hospital first used cells derived from iPS cells to treat macular degeneration. She extracted skin cells from a 70 year old female patient, induced them into iPS cells, cultured them into retinal cells, and transplanted them into the patient's eyes. Takahashi Yadai claimed that these cells survived for ten years, preventing further loss of vision in patients.

However, autologous cell therapy is time-consuming and expensive, with large cell sheets that require invasive surgery. Takahashi Yadai hopes to create a commercially viable therapy that uses mass-produced donor cells and finds less invasive implantation methods.

She attempted to implant the cultured 2 centimeter long and 200 micrometer thick cell strips into the retina through a small incision. The results released in March this year showed that the cells of three patients were still alive and safe one year after surgery.

This result may stem from the natural resistance of the retina to regeneration. Other parts of the eye may benefit greatly from cell therapy, such as the cornea, which is maintained and constantly rebuilt by a population of stem cells.

In November last year, the team of ophthalmologist Yuki Nishida from Osaka University implanted transplants derived from donor iPS cells into four patients, and three of them showed continuous improvement in vision. Its startup company Raymei plans to receive approval to conduct clinical trials within the next three years.

New progress in neural tissue regeneration

The regeneration of neural tissue has always been an important application direction of iPS cells, but it is also full of challenges.

In 2018, Jun Takahashi, director of the iPS Cell Research and Application Center at Kyoto University, led an experiment in which they used donor iPS cells to treat Parkinson's disease.

The results published in the journal Nature on April 16th showed that after two years of treatment, at least four patients showed significant improvement in symptoms, such as reduced tremors and stiff movements. A patient went from needing help to being able to live independently without taking conventional medication.

Another trial involving 12 patients also showed that their exercise ability improved after 18 months. Now, Jun Takahashi has turned his attention to developing cell therapies for treating stroke.

Stem cell scientist Eiyuki Okano from Keio University in Tokyo has demonstrated another potential use of iPS cells. Between 2019 and 2023, the Okano team treated four patients with spinal cord injuries using donor iPS cells. Preliminary results from March this year showed that one paralyzed patient was able to stand independently and was learning to walk, while another patient had some arm and leg muscles that could move but could not stand. The other two patients did not show significant improvement.

The Safety and Future of Stem Cell Therapy

Similar experiments are also being conducted outside of Japan. But Japan's approval process is relatively easy. In 2013, Japan introduced a system that allows for conditional approval of regenerative medicine products if they are proven to have no significant safety issues and may be effective. Some researchers have expressed concerns about Japan's rapid approval process and related projects. Last year, two conditionally approved products were withdrawn due to failure to demonstrate clinical efficacy or reproduce early trial results.

Although not yet fully approved, the iPS cell therapy industry has actively expanded its production capacity to meet the expected high demand. Sumitomo Pharmaceutical Company built the world's first donor iPS cell product manufacturing facility in 2018 and supported multiple early trials, including providing transplanted cells for Parkinson's disease trials.

However, the ultimate vision of iPS cell therapy is to return to the idealized state of autologous transplantation, aimed at reducing the risk of rejection, avoiding long-term use of immunosuppressive drugs, and addressing existing ethical concerns. Although more than 680 people worldwide have participated in trials of iPS cell-derived products, only 11 people have received autologous transplants.

Currently, stem cell therapy has been generally proven to be safe. Despite concerns that the process of creating iPS cells may increase the risk of cancer, there are safeguards in place to ensure that there are no residual pluripotent cells in the transplant, and cancer causing gene mutation screening is performed on the cells before transplantation. However, the fear still exists.

A recent experiment has also attracted attention. A 73 year old male plans to receive corneal inner surface cell transplantation from donor iPS cells for the treatment of eye swelling. Pre transplant sequencing revealed a deletion of the EP300 gene, which is considered a tumorigenic change. Although laboratory studies have shown that cells containing this mutation are less prone to tumorigenesis and no adverse events have been found, the researchers have decided to terminate the experiment.

This incident may prompt Japanese regulatory agencies to require all experiments to undergo whole genome sequencing of cells before transplantation. But more researchers still maintain confidence in stem cell therapy, believing that the significant investment in iPS cells will ultimately pay off.