Parkinson’s disease: how could stem cells help?
Parkinson's disease affects millions of people worldwide. Although the symptoms can be treated, there is no known cure. Scientists are investigating how regenerative medicine and stem cell science could be used to treat or prevent the disease.
Tremors, muscle rigidity and other symptoms of Parkinson’s disease (PD) are caused by the death of dopamine-producing neurons in the brain. Dopamine producing neurons throughout the brain are affected, but the ‘substantia nigra’ is the primary brain region where neurons are lost.
People affected by PD often develop abnormal protein clumps in their brain called Lewy bodies. These clumps are made of a protein called alpha-synuclein.
Levodopa (L-DOPA) is the primary drug used to treat PD. Levodopa is converted into dopamine when in the body, which compensates for lost dopamine-producing neurons.
Approximately 5% of people with PD have inheritable gene mutations linked to PD. Researchers are investigating what causes PD in the other 95% of patients in clinical studies, animal models and cell models.
Transplantation of young brain cells from human foetuses into people with PD has shown promising results in previous clinical trials. The current TRANSEURO study is re-examining this treatment method with the aim of minimising side effects and measuring efficacy.
Scientists can now make dopamine-producing neurons from both human embryonic stem cells (ESCs) and human induced pluripotent stem cells (iPSCs). Neurons made from human ESCs and iPSCs mature into human dopamine-producing neurons, survive and function after transplantation into mouse, rat and monkey models of PD.
Alpha-synuclein and many other proteins coded by genes linked to PD are still poorly understood. These genetic forms of PD still only make up a small proportion of patients. This makes it very difficult to understand the precise causes of PD.
Although the medications we have for PD are very useful, they begin to lose effectiveness after several years and as the disease progresses. Stem cell treatments potentially offer a way to provide new neurons that can replace the neurons lost to the disease. Stem cell treatments based in human ESCs and iPSCs are still not approved for the treatment of PD in humans, however the first clinical trials are expected to start in 2018. Studies in animal models of PD have demonstrated that human dopamine neurons from ESCs and iPSCs are safe, effective and similar enough to the original human nigral neurons. However, these still need to be shown that they are safe and beneficial to people with PD before they will be widely used.
People with Parkinson's disease don't have enough dopamine – a chemical that allows messages to be sent to the parts of the brain that control movement and some forms of thinking. The disease targets and kills dopamine-producing nerve cells, or neurons, in part of the brain called the substantia nigra, although the disease does affect other nerve cells within the brain which may account for some of the other features of Parkinson’s such as problems with sleep, motivation, thinking, etc. Parkinson’s is also linked to the formation of clumps of a protein called alpha-synuclein in the brain. These abnormal protein clumps are called Lewy bodies.
As dopamine nerve cells die, Parkinson’s patients develop tremors and rigidity, and their movements slow down. They might also lose their sense of smell or suffer from sleep disorders, depression, constipation and sometimes dementia in the later stages of the disease as the disease spreads out to involve other nerve cells.
Scientists are still baffled by what causes Parkinson's. In about 1 in 20 cases, it is caused by an inherited genetic problem that affects production of the alpha-synuclein protein. What causes the remaining 95 per cent of cases is not clear. It mainly affects people over 40 but can appear in younger people. Men are more at risk than women. Some research has made a link with pesticides, while smoking and coffee appear to reduce the risk of getting the disease, though it is not known why.
Current treatments for Parkinson’s include the drug Levodopa, which was discovered in the 1960s. It is converted into dopamine in the body, so it acts as a stand-in for the lost dopamine-producing neurons. Some other drugs act like dopamine to stimulate the nerve cells. Patients are also treated with occupational therapy, physiotherapy, healthy diet and exercise. Surgery, such as deep brain stimulation with implanted electrodes, is used to treat more advanced cases, especially in those where the drugs are working less well.
These treatments relieve the symptoms of Parkinson's disease, but do not slow down or reverse the damage to nerve cells in the brain. Over time, the clinical features get worse despite treatment. By the time patients are diagnosed with Parkinson’s they have often had the disease for years and have lost over half of the dopamine cells within the nigra. Tests that detect Parkinson’s earlier may help, but scientists are searching for a way to replace the damaged cells.
Although the underlying cause of Parkinson's disease is unknown, scientists do know which cells and areas of the brain are involved. Researchers are already using stem cells to grow dopamine-producing nerve cells in the lab so that they can study the disease, especially in those cases where there is a known genetic cause for the condition. Because a single, well-defined type of cell is affected, it may also be possible to treat Parkinson’s by replacing the lost nerve cells with healthy new ones.
Replacing lost cells
Doctors and scientists think cell replacement therapy will work because of the results of transplantation studies done in the 1980-90s. In particular, Swedish, American and Canadian researchers have transplanted the developing nigral dopamine-producing neurons from human fetuses into animals and human patients with PD, with major improvements in some cases but only modest changes in others. These initial studies led to bigger studies which then reported some side effects in some patients in receipt of such grafts in the form of involuntary graft induced movements - similar to those seen in many patients on long term L-dopa treatment. The basis for this is still debated but may relate to the transplantation of non-dopamine cells found in the human fetal midbrain grafts. In addition, it has also been noted that some patients have also developed some PD pathology in their grafts, even though the transplants are less than 20 years old. This has led to the suggestion that PD may involve a process of disease spread through the passing of abnormal forms of alpha synuclein from one nerve cell to another.
A new study, TRANSEURO, is looking again at fetal human dopamine transplants and aims to address issues of consistent efficacy and avoiding the side effects of the involuntary graft induced movements. This new study will involve a new clinical trial.
Scientists remain optimistic that introducing young cells into the brain could better treat Parkinson’s disease, but not enough fetal tissue is available to treat the large numbers of people with Parkinson’s, and the use of fetuses also raises ethical questions. So at the same time, they are looking at stem cells as an alternative source of new dopamine cells for Parkinson’s patients:
- Embryonic stem (ES) cells can be directed to make dopamine-producing neurons, which could be transplanted into patients. Dopamine-producing neurons have been made from both mouse and human embryonic stem cells in the laboratory, and the human cells have recently been shown to have similar effects as the fetal cells in a rat model of Parkinson’s disease.
- Induced pluripotent stem (iPS) cells can be made from a patient’s adult skin cells in the lab, and then used to make dopamine-producing neurons. Recent studies in rat and monkey models of PD have shown that dopamine-producing neurons survive and mature with good outcomes.
Understanding the disease and developing new drugs
Transplantation is not the only application for stem cells. Scientists are making iPS cells from patients with Parkinson’s disease, and using these stem cells to produce diseased neurons in the lab. The neurons act as a powerful tool to study how Parkinson’s disease works and to test substances that could be developed into new drugs to treat the disease.
Stem cell treatments for Parkinson's are still in the early stages of development of a clinical product. Some of the most important recent advances include work on methods for making dopamine-producing neurons in the lab; research on how to improve the effectiveness of transplants and avoid side effects; and studies investigating how the disease develops and how cells can help with the development of new drugs to stop this.
Cell replacement research: some recent examples
Researchers focussing on making dopamine neurons from stem cells for cell replacement therapy have recently formed a collation in order to share our expertise and information between the teams in order to bring a safer and more effective cell to clinical trial. G-FORCE PD, is the name of this collation that consists of world-leaders in the field from Japan, Sweden, UK and USA.
Our research in animal models of PD has so far show that human dopamine neurons made from ESCs and iPSCs can mature into the desired cell type, mature and function as dopamine neurons in animal models of PD, and importantly have not shown any ability to cause over-growths. Recently we have also demonstrated that the dopamine neurons we make in the lab are almost identical to those from the human fetus. We have protocols which allow us to produce large numbers of these human dopamine neurons from ESCs in a very precise manner – leading to a purer population of clinical-grade cells for use in clinical trials.
By sharing our results, we hope to start a number of clinical trials using both ESCs and iPSCs as soon as possible without compromising on the quality, efficacy and safety of the cells we are producing for the first-in-man clinical trials.
Disease and drug research: a recent example
Scientists are using iPS cells to investigate the genetic problems that make some people susceptible to Parkinson's. Tilo Kunath’s research group in Edinburgh, UK, is doing this by making iPS cells from a mother and daughter with a known genetic cause of PD. The mother has Parkinson’s, but her daughter did not inherit the genetic problem. By comparing the ability of the different iPS cells to make neurons and examining those neurons closely, the researchers hope to discover more about how the disease works and to find new drugs to treat it.
Stem cell therapies for Parkinson’s disease are not yet ready for use in patients. We have made significant steps in recent years, so much so that the first clinical trials are due to start in 2018. For now, the main challenges for scientists are:
- To find out how to grow neurons in sufficient quantities and at high enough safety standards to treat patients.
- To demonstrate that the neurons from stem cells are safe to use in people with Parkinson’s disease
- To demonstrate the same encouraging results we have observed in our animal models of PD in clinical trial
- To establish exactly how and where to transplant the cells so that they work properly in the brain without causing side effects.
This factsheet was created by Lou Robson.
Reviewed and updated in 2016 by Malin Parmar.
Reviewed and updated in 2018 by Malin Parmar and Shane Grealish.
Lead image of neurons grown from embryonic stem cells by Sally Lowell.
Picture of green nerve cells by Tilo Kunath. Dopamine-producing cells by Tilo Kunath and reproduced with permission from Devine MJ, Ryten M, Vodicka P, Thomson AJ, Burdon T, Houlden H, Cavaleri F, Nagano M, Drummond NJ, Taanman JW, Schapira AH, Gwinn K, Hardy J, Lewis PA, Kunath T. 2011. Parkinson’s disease induced pluripotent stem cells with triplication of the α-synuclein locus. Nature Communications 2:440. doi:10.1038/ncomms1453.