A trial is currently underway of iPS-cell derived dopaminergic cells
Global Trials Testing More-Advanced Neuronal Therapy for Parkinson’s Disease: Results from a Multi-Beta-Structured Brain
Cell therapies are designed to replace damaged neurons, but previous trials using fetal tissue transplants have had mixed results. The latest findings are the first among a handful of global trials testing more-advanced cell therapies.
Results published in March suggest that for three individuals who received the treatment, the cells have survived and are safe one year after surgery2. But the signs of benefit are mixed. One of the three individuals said she could see her husband’s face clearly for the first time in ten years, but only through a small section of her eye, where the cells had been transplanted.
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 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.
The results of both study represent good news for a large number of people. In 2021, some 11.8 million individuals worldwide were living with Parkinson’s3, more than double the number 25 years earlier. 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 sites across the putamen in both hemispheres, to fill up that region of the brain.
In order to have enough cells to survive the surgery, seven people received a lot of cells, with the hope that 100,000 and 300,000 would survive. A healthy brain has more than one million dopamine- producing neurons. immune-suppressing drugs were given to the recipients to prevent them from rejecting the transplant.
Brain scans show an increased production of dopamine even after the participants stop taking the immune-suppressing drugs.
On average, individuals who received the low dose showed a 9-point improvement in their symptoms on a standardized assessment for Parkinson’s disease, and those who received the high dose gained 23 points. The assessment is used to measure everyday activities, pain levels and sleep. 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.
Outcomes of MDS-UPDRS part III on PD05, PD04, and PD08: Importance of Stability and Mobility in a Young Population
Yamanaka discovered in 2006 that adult cells can be reprogrammed into an embryo-like state, capable of turning into almost any kind of tissue. Yamanaka became a household name after he won the Nobel Prize for Physiology or Medicine in 2012 and got huge success with his stem cell research. They are an example of the country’s global scientific ambitions.
300,000 and 150,000 cells were expected to survive, but three individuals got up to 5 million cells and four got up to 11 million. “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. They were given immune-suppressing drugs for 15 months.
Among the three patients (PD02, PD04 and PD08) who exhibited a beneficial effect on MDS-UPDRS part III, only PD02 showed improvement in both the off-time period and PDQ-39 scores. These evaluations are subjective and reflect the patient’s perceptions. It is possible that patients had very high expectations for this new treatment, and the results did not meet such high expectations despite objective improvements. In the remaining two patients (PD05 and PD06), motor deficits stabilized at a similar level of decline to those receiving conventional medication36,37. These two patients exhibited a higher degree of deterioration in motor symptoms compared with the other patients during the on-time, suggesting that faster neurodegeneration, especially in the non-dopaminergic systems, diminished the beneficial effects produced by the graft during the trial period. Recent studies show that younger patients with less severe symptoms may be suited for this treatment, and as a result, PD05 was 69 years old at the baseline. The efficacy of this treatment may be enhanced by refining patient eligibility criteria.
Some discrepancies were noted between the Hoehn–Yahrs stage and the part III scores. The Hoehn–Yahrs stage emphasizes mobility issues and the MDS- UPDRS part III gives a more in depth evaluation of motor symptoms in the disease. Improved stability and mobility may explain the greater improvement in the Hoehn–Yahr stage compared with the changes observed in the third edition of the MDS-UPDRS.
Development of a novel treatment for human iPS cells based on donor-derived cells as a medical tool to promote neurosyndroma
Scientists launched clinical trials and start-up firms. Large biotech companies swooped in, investing even more in manufacturing hubs. There will be a rush of patients from Japan and abroad. “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.
There is a need to raise awareness among both policymakers and the public of why careful and thorough evaluation of new science-based medical products is best for all concerned — patients, researchers and organizations taking such interventions to the clinic. It has been decades since researchers were able to bring regeneration medicine to the point of clinical application. Regulators around the world must not put that promise at risk by rushing the final stage of the process.
The public may be reticent to try this treatment because it costs too much, large trials have not yet shown clear clinical benefit, and safety is still a concern. We need to realize what the potential of these cells are, and what they can and cannot do.
Hideyuki Okano, a stem-cell scientist at Keio University in Tokyo, has demonstrated another potential trick for iPS cells. He and his colleagues used donor-derived cells to treat four people with spine injury over the course of two years. 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. One can use their arm and leg muscles, but cannot stand. Two others did not show substantial improvements.
But Takahashi wanted to create a commercially viable treatment. This meant a change in approach, using cells from donors that could be mass-produced, and finding less invasive ways of getting them into the eye.
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 “scientifically, the best treatment”.
The difficulties might come down to the retina’s natural resistance to regeneration. Stem cells keep the clear covering of the eye, so it’s possible that other areas of the eye might benefit from cell therapies.
Brain Regeneration Cell Development in Japan is a Problem for Mr. Takahashi, but Not for the Medicinal Officer (Mumamoto) Svendsen
Nishida has set up a company called Raymei which plans to launch a larger trial in three years, and is looking to gain formal approval in three years. The next trial is crucial according to him.
The regeneration of nerve tissue has been one of the great hopes for iPS cells, but it has been fraught with challenges. Jun Takahashi’s office is lined with statues of elephants and navy-blue samurai armour to encourage his lab.
But, unlike his wife, he has not set up a company to develop the technology for manufacturing the cells and conducting the surgery. Instead, he has instead transferred that knowledge to Sumitomo Pharma, based in Osaka. “As a scientist, I am kind of satisfied,” he says. He has now diverted his attention to developing cell therapies for treating stroke.
Japan has a fast-track process which can be used for rare conditions or have few other options. “In order to move this field forward quickly, you’re going to have to have an element of risk,” says Svendsen. In Japan, I have seen regulations put in place.
Treatments can be offered by companies, but the costs are covered by the national health system. They need to collect data on safety and effectiveness to get full clinical approval.
Although clearly riskier than the usual process, in theory, this system allows potentially life-changing interventions to be provided more quickly to people for whom alternative treatments aren’t available. This is one of the reasons why it is being watched closely around the world. There is a belief that regulation is holding back innovation. The early examples from the fast-track process suggest that speed must be kept to a minimum.
A Robotic Manufacturing Model for a Macular-Degeneration Treatment: Early-Phase Clinical Trials in the Study of Tumors and Rigidity
Masayo Takahashi has chosen a more portable manufacturing model for her macular-degeneration treatments: a white, muscular-looking, two-armed robot. The system checks on the progress of cells in the process of being prepared for transplant. The company can produce enough cells for more than 800 individual treatments in 4 months.
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 purpose of these trials is to assess whether a therapy could 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.
A recent study has shown that fetal tissue transplanted with human induced pluripotent stem cells improves symptoms in people with Alzheimer’s disease. The results suggest that for three people who received the treatment, cells survived and are safe one year after surgery. However, a researcher said that this metric is somewhat subjective and can be influenced by the placebo effect.