More than 6 million people have the highly debilitating Parkinson’s disease. Only the symptoms of Parkinson’s disease can be alleviated, and a promising cure has been unsuccessful. In contrast, stem cell transplantation offers a glimmer of hope. The first clinical trials involving patients will begin in 2021, and if these replicate the convincing results from preclinical studies in rats and pigs, stem cell treatment might be realistic in 5–7 years.
The early signs are shaking, stiffness and slower movements. The central nervous system of people with Parkinson’s disease degenerates slowly, and this often leads to difficulties in walking combined with sensory, behavioural and emotional problems. Daily medication can alleviate the symptoms, but the effect of the medicine diminishes around 7 to 15 years after disease onset, and most people with Parkinson’s disease then have severely debilitating symptoms that cannot be alleviated without severe side-effects. Today, more than 6 million people worldwide have Parkinson’s disease, and that number is increasing as global populations age. Researchers are therefore still struggling to understand and treat Parkinson’s disease, but so far all these efforts have been in vain.
“Unfortunately, a number of recent clinical trials of a treatment using GDNF, the prime candidate for a possible cure for Parkinson’s disease in the past 8 years, have failed. By contrast, developments within stem cell transplantation look very promising. We just started the final preclinical trials involving rats and pigs, and if there are no serious side effects, we expect to be able to embark on clinical trials involving people in 2021. If these succeed, this treatment may be available to people with Parkinson’s disease from 2026,” says Agnete Kirkeby, Associate Professor and Group Leader, Department of Neuroscience, University of Copenhagen.
One clinical trial after another has failed
More than 30 years have elapsed since researchers seeking the cause of Parkinson’s disease began investigating GDNF (glial cell–derived neurotrophic factor). The dopamine-producing neurons, a type of neurotransmitter essential for controlling human movement, degenerate in Parkinson’s disease. This can be easily treated with oral dopamine in the short term, but over time this becomes less and less effective as the side-effects increase. In the 1990s, researchers discovered GDNF.
“In animals, GDNF appeared to be able to protect the dopamine-producing neurons in the brain from cell death. Clinical trials were therefore quickly initiated. The first ones probably failed because of insufficient doses of GDNF being delivered to the brain tissue. Since then, one clinical trial after another has failed; each time the suspected reason was that either the disease had progressed too far or that the doses were too low to be effective,” explains Agnete Kirkeby.
However, expectations were high for the latest clinical study from the Bristol Medical School at the University of Bristol, which generated considerable publicity, including a BBC documentary The Parkinson’s Drug Trial: A Miracle Cure? Nevertheless, once again, the results were disappointing. Admittedly, GDNF treatment seemed to improve the motor abilities of people with Parkinson’s disease, but unfortunately the difference from the control group was not statistically significant.
“This may seem paradoxical, but the general problem in these studies is probably that the participants become better at solving the tasks as time goes on, so that everyone learned the same skills whether they received the medication or were in the control group. Although another trial set-up might have revealed an effect of the treatment, I am pretty convinced that, if GDNF really were a miracle cure, then we would have seen clear effectiveness already,” says Agnete Kirkeby.
The right cocktail
Instead, Agnete Kirkeby is counting on stem cell transplantation, another type of restorative treatment for Parkinson’s disease. In 2012, Agnete Kirkeby and her colleagues at Lund University in Sweden made a major breakthrough when they produced new dopamine-producing neurons from stem cells. They showed that transplanting these cells into rats’ brains completely counteracts the motor symptoms of Parkinson’s disease. However, being able to apply this to patients was a long way off.
“At that time, we could produce the stem cells with a purity of 60–70%, which may sound high, but when the cells need to be transplanted into a person’s brain, safety is extremely important. We then set the goal of achieving 90% purity in our production method before seriously considering transplantation into humans,” explains Agnete Kirkeby.
Understanding the challenge the researchers faced requires understanding the process of producing stem cells. In principle, all stem cells can move in all directions and thus become all types of cells, but they develop in one direction or another depending on the growth factors that affect them and the environment in which they grow. The stem cell researchers therefore needed to imitate as precisely as possible what happens during fetal brain development.
“We grow the cells in small petri dishes, and if we change the concentration of a single chemical by just 10%, then the cells develop in a completely different direction than we intended. We have therefore not only had to ensure the right growth conditions for the past 12 years. We have also had to be able to replicate the same conditions again and again so we were certain that the method was reproducible,” says Agnete Kirkeby.
In the right direction
Agnete Kirkeby moved to the University of Copenhagen, and together with her former colleagues at Lund University, she succeeded in 2017 in producing the dopamine-producing stem cells with such purity and safety that the method was ready for transferring to human patients. These results were published in Nature Protocols.
“This was a massive and crucial breakthrough, because we showed that the method could potentially be used on humans and not just on rats. The reason why we still had some way to go was because we needed to be absolutely sure that we were not doing more harm than good. The stem cells must enter the brain at the right time and in the right place,” explains Agnete Kirkeby.
Transplanting the cells prematurely risks them not developing in the right direction, but transplanting them too late means that they may continue to divide. This may develop tumours.
“We have not yet observed any tumours in any of the rats subjected to transplantation, but the public authorities require us to conduct further long preclinical trials to investigate whether the transplantation has any side-effects,” says Agnete Kirkeby.
Agnete Kirkeby and her colleagues are not permitted to conduct these last preclinical studies themselves. These must be performed at a Good Manufacturing Practice (GMP) facility in England. The protocols must therefore be so precise that others can replicate the cell culturing and transplantation with the same precision and results.
“Training the personnel to carry out the transplantation has been especially challenging, since a microlitre of stem cells needs to be transplanted into four very specific locations in the brain. The locations must be pinpointed using stereotactic coordinates so that the personnel know exactly where to place the cells, regardless of how large the brain is. Then the transplantation should preferably take place quite quickly so that the cells and the rat are not harmed. Transferring this method to a completely different team that has not tried it before is certainly not easy,” explains Agnete Kirkeby.
20–30 more years
However, the training has been successful and the last preclinical studies involving rats have started in England. Further positive results without side-effects will pave the way for the first clinical trials next year involving Parkinson’s disease patients.
“Right now we just have to wait – and hope that the trials are not put on hold because of the COVID-19 situation. If we are allowed to start the clinical trials involving people next spring, two rounds of clinical trials over about 5 years will be required before we have a cure for Parkinson’s. The aim is to treat each person with a single transplantation that will last a lifetime,” says Agnete Kirkeby.
Unfortunately, since the cause of Parkinson’s has not been established, the researchers are fully aware that they risk that the disease may attack the transplanted cells inside a person’s brain. However, the researchers are optimistic about the lasting nature of the treatment.
“Everything indicates that the dopamine-producing cells of people with Parkinson’s slowly degrade over 20–30 years and become highly susceptible to the disease as they age. Transplanting stem cells is equivalent to receiving cells from a newborn, and we therefore believe that these cells have the resilience to survive many years in the person’s brain. If all goes well, we hope that a stem cell treatment can be marketed in 5–7 years, so that we can finally repair people’s brains rather than alleviating the symptoms of Parkinson’s,” concludes Agnete Kirkeby.
“Parkinson disease and growth factors — is GDNF good enough?” has been published in Nature Reviews Neurology. “Extended treatment with glial cell line–derived neurotrophic factor in Parkinson’s disease” has been published in the Journal of Parkinson’s Disease. In 2018, the Novo Nordisk Foundation awarded a grant to Agnete Kirkeby for the project Mapping Human Neural Lineages in a Novel In Vitro Model of the Developing Neural Tube Built with Morphogenic Gradients.