The standard treatment today for the 800 million people who have Parkinson’s disease is medication. Unfortunately, this gradually becomes less effective over time while generating increasingly more side-effects. After a decade-long collaboration between researchers in Denmark, Sweden and the United Kingdom, the first person with Parkinson’s has now received a milestone stem cell–based transplant in a new clinical trial. The operation was completed as expected, and now 1 year of intensive follow-up of the eight trial participants will determine whether stem cells may be a safe treatment for this currently incurable disease.
Parkinson’s often starts with fairly common symptoms: sleep problems, restless legs, constipation, loss of smell, and later stiffness and tremors. All these can occur as a result of normal ageing, but for some people these symptoms foreshadow a disease that slowly breaks down certain types of brain cells – Parkinson’s disease. The cells that break down are located deep in the brain and produce dopamine, a signal substance. When these cells die, people have problems initiating and controlling movement and some patients may also gradually develop cognitive problems.
As the dopamine-producing cells die, the brain cells lose the ability to communicate properly. Today, no treatment can repair or replace the diseased nerve cells. “We expect to use our new stem cell–based treatment to replace the nerve cells that are lost in the brains of people with Parkinson’s disease. We hope that a single treatment can lead to lifelong improvement of the symptoms. If it works, then this will be a huge breakthrough,” explains STEM-PD preclinical development lead, Agnete Kirkeby, Associate Professor at the Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW) and Department of Neuroscience, University of Copenhagen and Lund University, Sweden.
Stem cells replace the patients’ own brain cells
Agnete Kirkeby and colleagues have been developing this treatment for more than 10 years, determining how to apply the stem cells step by step. The starting-point for the treatment is embryonic stem cells, which come from a fertilised egg from a fertility clinic, but the stem cells can become any type of cell: skin cells, liver cells, brain cells or others.
“We have had to teach ourselves to manage the process so that the stem cells develop specifically towards becoming dopamine-producing nerve cells. This requires various growth factors that can make them develop in the right direction from the stem cell stage,” says Agnete Kirkeby.
The treatment does not save the person’s original dopamine-producing cells. Many of these are already lost as part of the ongoing disease process in the brain. Instead, the researchers insert new dopamine-producing cells into the brain that develop from stem cells in the laboratory through a very special method the researchers have developed.
“Based on our experiments in animals, we think that the treatment can also work for people. In experiments on rats, the treatment completely eliminated the motor symptoms of Parkinson’s disease. We are therefore excited to follow the trial participants to see whether we can observe similar signs of clinical efficacy in humans,” explains Agnete Kirkeby.
Rigorous preclinical tests
The ultimate goal for the researchers is that a single STEM-PD treatment will enable people with Parkinson’s disease to become independent of symptom-relieving medication for the rest of their lives.
“Based on our promising results in animal experiments, the Swedish Medical Products Agency last year approved the first clinical trial involving humans with STEM-PD as a test treatment of initially eight people,” says Agnete Kirkeby.
And on 13 February 2023, the STEM-PD stem cell–based product was administered for the first time to a person with Parkinson’s at Skåne University Hospital in Sweden.
“After the dopamine-producing cells are produced in the laboratory, they are frozen in liquid nitrogen. Immediately before transplantation, the cells are thawed again and a neurosurgeon carefully transplants the cells into the person’s brain,” explains Agnete Kirkeby.
As small as 4 millimetres
The transplantation is a complicated procedure in which the person’s brain is first scanned so that the surgeon can calculate exactly where to place the cells to ensure that they can cover the entire area of the brain that has insufficient dopamine.
“The surgeon infuses the cells with a thin needle through a small hole in the skull and places them in very specific places in the brain of the person that has lost the dopamine-producing cells. After the transplantation, the cells are expected to mature into new and healthy nerve cells in the brain and are expected to make contact with the person’s own nerve cells,” says Agnete Kirkeby.
“The brain region into which the cells are transplanted in this trial can be as narrow as 4 millimetres. The surgical instrument therefore has a very high level of precision, and we are greatly helped by modern imaging techniques,” explains consultant neurosurgeon Hjálmar Bjartmarz in a press release issued by Lund University.
Gesine Paul-Visse, the consultant neurologist in the study, says in the press release: “This is an important milestone on the way to a cell therapy that can be used to treat people with Parkinson’s. The transplantation has been carried out as planned, and the correct location of the cell implant has been confirmed through MRI.”
Expected to be safe and without side-effects
Researchers in Japan and the United States have developed two similar stem cell products in parallel that are currently in clinical trials in Japan and the United States on seven and 12 people with Parkinson’s, respectively.
“There are important differences in the production methods for the three products, but basically all three replace the dopamine-producing nerve cells in the brain. An important difference in our study is that we only treat people who are younger than 75 years and have moderate Parkinson’s, in contrast to the trial participants in the United States and Japan, who are treating patients in more advanced stages of the disease,” explains Agnete Kirkeby.
By testing on younger, moderately ill people, Agnete Kirkeby hopes that the treatment will have a better chance of effectiveness. However, none of the research groups yet have results for effectiveness.
“With the first eight participants, we aim to confirm that the treatment is safe and feasible to administer. As soon as we know this, we can hopefully be allowed to transplant the stem cells into more people in a new and larger study focusing on evaluating the efficacy of the treatment,” says Professor Malin Parmar, who leads the project from Lund University.
Any potential effects of the STEM-PD product may take several years to evaluate. The researchers will follow the participants who have undergone transplantation closely, and cell survival and potential beneficial effects will be assessed in the coming years.
“Reaching full effectiveness can take up to 2–3 years because the transplanted cells must mature and send out many long-range nerve fibres to communicate effectively with the other brain cells,” explains Malin Parmar.
Not necessary to match the donor
In the meantime, while the transplanted cells fully mature in the brain, the researchers hope that the participants can gradually be weaned off their daily medication.
“Another question that the study needs to clarify is the dose of stem cells required to optimise effectiveness. However, no clinical data or results will be communicated until sufficient material from the clinical trial has been collected and analysed in accordance with regulations on healthcare confidentiality,” says Agnete Kirkeby.
The treatment is initially primarily intended for people diagnosed early in life who, without the treatment, can look forward to living with Parkinson’s for 30–40 years – often with increasingly poor quality of life. If the treatment is effective, however, it could eventually be extended to treat more people.
“The stem cell–based treatment has been developed so that it works for everyone with Parkinson’s. Further, the donor’s and recipient’s immune systems do not need to be matched. However, for about 1 year after the transplant, immunosuppressive drugs are required to prevent the brain from rejecting the new cells. After that, we hope that the transplanted stem cells will become a natural part of the brain’s cell tissue,” concludes Agnete Kirkeby.