Pioneering stem-cell trials in Japan report promising early results

"The country has invested hundreds of millions of dollars into research on induced pluripotent stem cells to treat diseased organs.

Some of the first trials to test whether reprogrammed stem cells can repair diseased organs have begun to report positive results. Research teams involved in the studies, all based in Japan, say they provide early hints that the hotly anticipated technology works. But many researchers outside the country are cautious about overstating the significance of the trials, saying they were small and the results have yet to be peer reviewed.

Induced pluripotent stem (iPS) cells are those that have been reprogrammed from mature cells — often taken from the skin — into an embryonic-like state. From there, they can then turn into any cell type and be used to repair damaged organs.

In January, researchers reported in a preprint¹ that the first person in Japan given a transplant of heart-muscle cells made from reprogrammed stem cells had experienced improved heart function following the procedure. Then, in April, another group announced that several people’s vision had improved after their diseased corneas were transplanted with corneal cells made from reprogrammed stem cells — a world first.

Ongoing trials are “delivering encouraging first insights into the evolution of iPS-cell-based therapies, from lab to patient”, says Wolfram-Hubertus Zimmermann, a pharmacologist at the University Medical Centre Göttingen in Germany.

The biggest impact of the iPS-cell trials in Japan so far is that they “give people confidence all over the world that it is doable”, says Kapil Bharti, a translational stem-cell researcher at the US National Eye Institute in Bethesda, Maryland.

Great expectations

The iPS-cell field is hugely popular in Japan, in large part because it was a local scientist, Shinya Yamanaka at Kyoto University, who discovered how to make the cells. Expectations for the potential uses of iPS cells soared in 2012, when Yamanaka won the medicine Nobel prize for his 2006 discovery. In 2013, the Japanese government announced that it would pour ¥110 billion (US$814 million today) over the next ten years into regenerative medicine.

In that time, Japanese scientists have launched at least ten trials in people. These have largely shown that the technology is safe, but have yet to establish that it has a beneficial effect. Now, public enthusiasm has waned, which threatens future government funding, says Masayo Takahashi, an ophthalmologist and president of the cell-therapy company Vision Care in Kobe, Japan.

“iPS-cell technology has only been around for 16 years. And bringing it into clinical testing has happened unbelievably fast,” says Zimmermann. “The challenge is that this is all happening under high public attention.”

Treating vision loss

The cornea study was designed to treat people who have severe visual impairments because they lack the stem cells needed to repair the cornea. Starting in 2019, ophthalmologist Kohji Nishida at Osaka University in Japan used donor-derived iPS cells to create sheets of corneal cells, which were implanted into one eye in each of four participants.

Nishida’s trial is not the first to use iPS cells to repair eye disorders. From 2014, Takahashi led two studies using iPS cells to treat seven people with macular degeneration^2,3, a condition in which eyesight deteriorates progressively. In those studies, the retinal cells seemed to survive the transplants and the participants’ vision did not get worse — a sign of success, says Takahashi. But scientists say it is difficult to show whether the cells contributed to slowing vision deterioration.

At a press conference on 4 April, Nishida reported the first evidence that iPS-cell treatment had improved vision. Three participants had markedly improved vision a year after their operations — a fourth participant’s sight remained mostly the same because they had cataracts. Nishida also reported data on the vision improvement. He says the initial disease has not returned in any participant, some of whom had surgery more than two years ago; this suggests the cells survived the transplant. He is preparing a manuscript for publication and peer review, and he plans to start a larger trial, with more than ten participants.

Encouraging result

Researchers outside Japan say the cornea trial is too small to establish the treatment’s effectiveness, but they are encouraged by the results. “I’m sure the patients are seeing better and that is a good sign,” says Bharti, who is leading a trial of a treatment for macular degeneration using reprogrammed stem cells. But, he says, “we should be careful to not call these efficacious trials”.

In Japan, the observed beneficial effect of the cells has boosted scientists’ morale. “I’m very happy that the cornea could show that now,” says Takahashi. The results are very important for regenerative medicine in Japan, she says.

There are also promising signs from another ongoing trial, in which donor cells are reprogrammed into heart-muscle cells, says trial leader Yoshiki Sawa, a cardiac surgeon at Osaka University. In his preprint posted in January, he reported results on the first of three people to receive the treatment¹. Sawa now says that all three — aged in their fifties, sixties and seventies — have recovered and are working. He aims to recruit another five participants by the end of this year.

The case report is important and it is good to see that the trial participant did not develop tumours or an irregular heartbeat, says Zimmermann, who is also running a trial using iPS-cell-derived heart muscle cells. But it is not clear whether any observed improvements in symptoms were a direct result of the transplanted cells or due to other aspects of the surgery. The participant received a low dose of cells, and those cells would not have survived beyond the three months that immune-suppressing drugs were administered, he says. “It is not a dramatic improvement; it is a stabilization.”

Still, researchers in Japan say the trial results come at a crucial time: the government’s 2013 investment in the field is due to end next year, and the cornea result in particular might help to justify continued investment in the technology.

Takahashi has heard that the government’s next budget for regenerative medicine will be reduced, which will have a flow on effect. In Japan, there are currently too many people in the field for the amount of investment that’s available, says Jeanne Loring, a stem-cell researcher at Scripps Research in La Jolla, California. “Not everybody can sort of break through.”

Industry support

Researchers still face other hurdles, too; chief among them are reducing the costs of producing the cells, and getting industry support to take the technology beyond small studies and trials. Koji Eto, a cell biologist at Kyoto University, who is leading a trial involving blood platelets derived from iPS cells, says many clinical trials will probably not raise the funds needed for commercialization, and will have to shut down.

To get industry support, scientists need to show that the therapies work, says Jun Takahashi, a neurosurgeon at Kyoto University. Results from ongoing clinical trials will be crucial, he says.

He is involved in one trial expected to report results soon, in which researchers used donor-derived iPS cells to generate neurons that produce dopamine. They implanted these into the brains of seven people with Parkinson’s disease between 2018 and 2021. Takahashi says that no severe adverse events have been observed so far. Participants are being observed for two years after surgery, and their neurological symptoms will be assessed, with results expected in 2024. “The best scenario is that the patients’ symptoms get better,” he says.

If Jun Takahashi’s and Sawa’s trials demonstrate strong evidence of clinical efficacy without side effects, the treatments could become the first to get conditional approval to be sold in Japan, as part of the government’s fast-track programme for regenerative medicines." [1]

 

The biggest advantage of iPS cells is that if the iPS cells are obtained from the skin of the same patient into which the healing cells are injected, the patient does not receive cells from a foreign body. Then why are prescribed immunosuppressive drugs?

 

1. Pioneering stem-cell trials in Japan report promising early results. Smriti Mallapaty, Nature 609, 235 (2022)