Fast approval of iPS-cell-based treatments of Parkinson’s disease within a year after surgery: More than 60 million stem cells in Japan

More than 60 iPS-cell clinical trials are in progress worldwide, with one third of them in Japan. The treatments have proved to be safe and shown signs of benefit. Moreover, the technology has been improving apace, says Shimmura. Japan could be the first country to approve iPS-cell-based treatments due to a fast-track approvals process. This could happen within a year for Parkinson’s disease.

Results published in March suggest that for three individuals who received the treatment, the cells have survived and are safe one year after surgery2. There are some signs of benefit. One of the three people was able to see her husband again for the first time in ten years thanks to a small portion of her eye that had been used to transplant cells.

The trials were mainly designed to test safety and were small, involving 19 individuals in total, which is not enough to indicate whether the intervention is effective, says Parmar.

Some people got better, while others weren’t, due to the relatively small amount of cells transplant in these early-stage trials.

The results from both studies represent welcome news for a large number of people. There were more than a million individuals living with Parkinson’s in the year 2021, up from under a million in 1991. The numbers are increasing, and could reach 25 million in the next quarter of a century, according to a modelling study published by The BMJ 4.

The stem cells were injected to 18 different locations across the putamen in both hemispheres to fill up that region of the brain.

A group of individuals received a lot of cells in an attempt to get 100,000 and 300,000 cells to survive the surgery. A brain with 300,000 dopamine-Producing neurons is healthy. The recipients were given immune-suppressing drugs to prevent them from rejecting the transplant.

Brain scans showed an overall increase in dopamine production, suggesting that some neurons survived the entire 18-month observation period, even after the participants stopped receiving immune-suppressing drugs.

Individuals who received the low dose show a 9-point improvement in their symptoms on a standardized assessment, and those who received the high dose gain 23 points. The assessment measures individuals’ daily life activities, pain levels, sleep and eating. Agnete Kirkeby, a stem-cell scientist at the University of Copenhagen who is involved in a European trial, points out that this metric is somewhat subjective and can be influenced by the placebo effect, but says the results warrant larger trials.

Induced pluripotent stem cells: How to make a human cell into a primitive state and how to use it for personalized treatment of damaged tissues

In 2012, the discovery of a way to ‘reprogram’ mature mouse and human cells into a primitive state from which they could develop into any of the body’s cell types won Shinya Yamanaka, a biologist at Kyoto University in Japan, a half share of the Nobel Prize in Physiology or Medicine. His demonstration of how to make these cells, known as induced pluripotent stem (iPS) cells, also raised hopes that personalized treatments could soon follow, to regenerate damaged tissues such as those of the eye, brain and spine.

Three individuals received up to 5 million cells and 4 received up to 11 million cells, of which 150,000 and 300,000 cells, respectively, were expected to survive. The leader of the trial says low survival rate is a big problem and needs to be solved. They were given the drugs for 15 months.

Scientists started clinical trials and start-up firms. Large drug companies invested more in manufacturing hubs. A lot of patients are going to come from Japan and other places. “Regenerative medicine in Japan is moving very dramatically,” says Masayo Takahashi, an ophthalmologist at Kobe City Eye Hospital and president of the biotechnology company, Vision Care. In 2014, she became the first to treat someone with cells derived from iPS cells.

Many countries are examining how to get drugs to market more quickly. Japan is currently in the spotlight, with a slew of its universities, companies and funding bodies preparing to apply for fast-tracked regulatory approval for certain products based on iPS cells, in some cases perhaps even within the year, as we report in a News Feature.

The public is not likely to give this treatment a try without first seeing clear benefits, treatment costs are high and there are concerns about safety. “We’re down to realizing what the potential of these cells are, and what the limits are,” Shimmura says.

An iPS cell trick was demonstrated by Hideyuki Okano, a scientist at Keio University. He and his colleagues used donor-derived cells to treat four people who had injured their spine. The researchers presented preliminary results — not yet peer reviewed — at a press conference in March, showing that one individual with paralysis can now stand independently and is learning to walk. A person can get their arm and leg muscles moving but can’t stand. Two others did not show substantial improvements.

When they attempted to inject a pool of donor-derived cells under the eye, they were unsuccessful. But the researchers had limited control over where the cells grew. They next tried growing strips of cells, 2 centimetres long and 200 micrometres thick. They used a tube to slide a few strips onto the retina, in hopes that it would allow them to expand into sheets.

It was a procedure with practical limitations, however. Self-derived, or ‘autologous’, cell therapies are time-consuming and expensive to make, and the large cell-sheets that researchers crafted for implantation required intrusive surgery. Takahashi says she chose this approach to ensure the highest chance of clinical benefit — to demonstrate to the world what was possible. It was designed to be the best treatment.

The problems may be caused by the retina’s natural resistance to regeneration. Stem cells maintain the cornea, the clear covering that let light in, so it might benefit from cell therapies.

Raymei: a giant, floating silver box for iPS-cell manufacturing and rare conditional approvals for Parkinson’s disease

Nishida is setting up a start-up company called Raymei, which will attempt to gain formal approval in three years. “The next clinical trial is pivotal,” he says.

One of the great hopes for iPS cells is the regrowth of nerve tissue. Jun Takahashi, husband to Masayo, has an office lined with statues of elephants and an imposing, life-sized set of navy-blue samurai armour, “just to encourage my lab”, he says.

Even without approvals in hand, the industry is building capacity in the expectation that demand for these treatments will be high. The new facility is believed to be the world’s first manufacturing facility for iPS-cell products. The building, in Osaka, looks like a giant, floating silver box. In 2020 it received the first cells for transplant, for the fourth participant in the Parkinson’s trial. The company is also supporting two early-stage Parkinson’s trials in the United States.

Some people are not worried about the fast-track process for rare conditions in Japan. “In order to move this field forward quickly, you’re going to have to have an element of risk,” says Svendsen. It has been reasonable in Japan, with their putting regulations in place.

Companies can offer the treatments, with costs mostly covered by the national health system. But they must continue to collect data on safety and efficacy to earn full clinical approval.

The fast-track system also incentivizes companies to roll out as many interventions as possible before a product’s conditional approval expires, maximizing potential revenue. It has led to calls for efficacy requirements for approval to be raised.

Macular degeneration using a white, muscular-looking, two-armed robot: The role of early-phase clinical trials in improving patients’ outcomes

Masayo Takahashi has chosen a more portable manufacturing model for her macular-degeneration treatments: a white, muscular-looking, two-armed robot. It checks in on the progress of cells as they are prepared for a transplant through a microscope. In 4 months, it can produce enough cells for more than 800 individual treatments.

The two studies published this week offer hope for people with a disease that is currently only manageable; there is no cure. Such early-phase clinical trials are a crucial part of both the research and the regulatory journey. The following trials are designed to evaluate whether a therapy can benefit patients.

Both studies, which are reporting the results of early-stage clinical trials, show that the interventions were safe, and that, on average, the recipients experienced measurable improvements in typical symptoms such as tremor and rigid movements.

“If we’re missing neurons, we’re able to replace them,” Tabar says. The expectation is that the cells are not capable of releasing a substance like dopamine. They’re going to rebuild circuitry.”

“They’re going to be there for a long while,” he says. “So you have to follow up and see if there is tumor formation or something of that nature.”

Neuron progenitors as precursors of human stem cells for a cure of Alzheimer’s disease in the early stage of the brain

The stem cells are supposed to connect with other cells in the brain.

There was a challenge of packaging many stem cells that could be delivered to surgeons. So researchers developed techniques that allowed them to freeze stem cells until they were needed.

“It took us nearly 10 years to figure out the recipe, how to make specifically those dopamine cells,” he says. “It took us another 10 years to have the product that we would dare to put into patients.”

A low or high dose of stem-cell therapy was administered to surgeons. Stem cells were derived from human embryons and converted into immature brain cells called neuron progenitors.

The results indicate that “now we have the potential to really, really halt this disease in its tracks,” says Dr. Mya Schiess, a neurology professor at UTHealth Houston who was not involved in either study.