Stem-cell therapies should not be rushed
Early-stage studies of the effect of embryonic stem cell treatment on the aging and mobility of infants and infants in the United States
Results of a study published this week show that at least four individuals saw noticeable improvements in their symptoms two years after the treatment. One went from requiring assistance to being able to live independently when not taking their regular medications. It was found in another trial that there were moderate improvements in movement after 12 individuals received neural progenitors from embryonic stem cells. Knowing that the treatment could work brought a lot of relief to Takahashi.
The studies, published by two groups in Nature today, are “a big leap in the field”, says Malin Parmar, a stem-cell biologist at Lund University, Sweden. Cell products show signs of life and are safe.
Parmar says that the trials were mainly designed to test safety, and that there is not enough to say whether the intervention is effective.
“Some people got slightly better and others didn’t get worse,” says Jeanne Loring, a stem-cell researcher at Scripps Research in La Jolla, California, which could be due to the relatively small number of cells transplanted in these first early-stage trials.
Development of induced pluripotent stem cells for Parkinson’s disease with the help of immunosuppressed dopamine-producing neurons
About 1 million people in the United States are living with Parkinson’s, a brain disease that attacks neurons that make dopamine. As those neurons die, patients can develop a range of disabling symptoms, including tremor, rigidity, fatigue, difficulty walking and cognitive problems.
The stem cells were injected to 18 sites across the putamen in both hemispheres — “to roughly fill up that region of the brain”, says Viviane Tabar, a neurosurgeon at the Memorial Sloan Kettering Cancer Center in New York City who conducted the US surgeries.
100,000 and 300,000 cells were the hope of the seven individuals who received a dose of 0.7 million cells. A healthy brain typically has 300,000 dopamine-producing neurons. The recipients of the transplant were given immune suppression drugs for a year to prevent their bodies from rejecting the transplant.
Brain scans suggested an increase in dopamine production even after participants stopped taking immune-suppressing drugs.
For a typical Parkinson’s patient, “you would expect every year to get two to three points worse,” says Dr. Lorenz Studer, who directs the Center for Stem Cell Biology at the Sloan Kettering Institute in New York and is a scientific adviser to BlueRock.
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. “This low survival rate is a big problem that needs to be solved,” says Jun Takahashi, a neurosurgeon at Kyoto University in Japan, who led the trial. Participants were given immune-suppressing drugs for 15 months.
Using donor-derived cell therapies in Japan to improve the ability of a person with paralysis to stand and walk on their own without using their own
Japan is brimming with signs of an approaching medical revolution. A state of the art hospital is preparing to begin taking patients, with rows of incubators humving in the new facility, and Shiny white robots tending dishes of cells.
Between 2015 and 2021, two cell-based regenerative-medicine products and two gene therapies were granted conditional approval in Japan under the same system. Safety does not seem to have been an issue, but two of the products did not meet the efficacy requirements for full approval and were withdrawn from the market last year. The performance of the other two is not yet known. They will need to meet the full efficacy requirements in the next few years if they are not to be withdrawn5.
But those approvals are not yet in hand, treatment costs are high, large trials showing clear clinical benefit have yet to materialize, and concerns about safety could still sap the public’s willingness to try this treatment. “We’re down to realizing what the potential of these cells are, and what the limits are,” Shimmura says.
Hideyuki Okano, a stem-cell scientist at Keio University in Tokyo, has demonstrated another potential trick for iPS cells. Between 2019 and 2023, he and his colleagues used donor-derived cells to treat four people with spinal-cord injury. The results of preliminary research presented at the March press conference show that a person with paralysis can stand and walk on their own. One can use some of their arm and leg muscles, but cannot stand. Two people did not show significant improvements.
She and her team initially tried injecting a pool of donor-derived cells just under the retina, where they might form sheets on their own. But the researchers had limited control over where the cells grew. They attempted to grow strips of cells that were 2 centimetres and 200 micrometres thick. They used a tube to slide several of these strips onto the retina through a tiny incision in the eye, in the hope that they would expand into sheets.
It was a procedure with practical limitations, however. It takes a long time and money to create and make self-derived cell therapies and the large cell-sheets 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 “scientifically, the best treatment”.
The retina might be the subject of some difficulties. But other parts of the eye might benefit more from cell therapies: the cornea, the clear covering that lets light in, is maintained by a pool of stem cells and constantly being rebuilt.
Developing neurosurgery cell therapies for stroke: A case study of Nishida, a neurosurgeon, and his wife Takahashi
Nishida has since set up a start-up company, Raymei, which plans to launch a larger trial and aims to gain formal approval in three years. He says that the next clinical trial is important.
Takahashi is a neurosurgeon and the director of Kyoto University’s Center for iPS Cell Research and Application (CiRA), an institute established by Yamanaka as a hub for iPS-cell research.
Unlike his wife, he has not set up a company to develop the technology for manufacturing the cells. Instead, he has instead transferred that knowledge to Sumitomo Pharma, based in Osaka. He says he is kind of satisfied as a scientist. He has now diverted his attention to developing cell therapies for treating stroke.
The fast- track process has raised concerns among some researchers in Japan. Last year, two of the four products that had received conditional approval under this mechanism — one involving thigh-muscle cell transplants for the heart, the other a gene therapy to treat ulcers in narrowed arteries in the limbs — were withdrawn. The first was rejected for formal approval after nearly a decade on the market because it failed to show clinical benefit. The second was withdrawn about five years after being conditionally approved, because surveillance data did not reproduce results observed in earlier trials.
Companies can offer the treatments, with costs mostly covered by the national health system. They need to collect more data on safety and effectiveness to get approval.
The fast-track system gives companies incentives to roll out interventions as soon as possible in order to maximize revenue. This has led some to call for the efficacy requirements for conditional approval to be raised.
Robotic Manufacturing of Blood Stem Cells for Masayo’s Treatments – How Do We Get Our Brains and What Do We Need to Do?
A white, muscular-looking, two-armed robot has been chosen as a portable manufacturing model for Masayo’s treatments. Powered by machine learning, it checks in on cells’ progress as they are prepared for transplant through a microscope. It can make enough cells for 800 treatments in 4 months.
Such work has the potential to transform lives, but it is important that these therapies do not move into the clinic too quickly. Researchers must be allowed to take as much time as is necessary to complete safety and efficacy tests.
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. These cells are not going to function as dopamine-releasing cells, and that’s the full expectation. They’re going to rebuild circuitry.”
“They’re going to be there for a long time,” he says. You have to check if there is tumor formation or something of that nature.
Dr. Tabar is a stem-cell scientist at the Memorial Sloan Kettering Cancer Center where she is the chair of neurosurgery.
Another challenge was creating and packaging large numbers of stem cells that could be easily 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.”
Surgeons administered either a low or high dose of a stem-cell product from BlueRock Therapeutics, a subsidiary of biotech and pharmaceutical giant Bayer. The treatment was derived from human embryonic stem cells, which researchers had coaxed into becoming immature brain cells called neuron progenitors.
According to Dr. Mya Schiess, a neurology professor at UTHealth Houston, the results show that we could stop the disease in its tracks.
The results of a clinical trial have shown that some Parkinson’s disease patients showed moderate improvements in their movement after receiving neural progenitors from human embryonic stem cells. However, it was found that others didn’t get any improvement. It was found in another trial that there were moderate improvements in movement after 12 individuals received neural progenitors from embryonic stem cells.