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.

Five per cent of people with PD have inheritable gene mutations linked to PD. Researchers are investigating what causes PD in the other 95% of patients.

Transplantation of young brain cells from human foetuses into PD patients has shown promising results. 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 induced pluripotent stem cells (IPSCs) and embryonic stem cells (ESCs). Neurons made from ESCs survive and function after transplantation into mice and monkeys.

Alpha-synuclein and many other proteins coded by genes linked to PD are still poorly understood. This makes it very difficult to understand the precise causes of PD.

Stem cell treatments are still not ready or approved for human treatment. Before they can be used, studies must clearly show that lab-grown neurons are safe, effective and similar enough to the original nigral neurons.

To use stem cells, procedures must be developed to create the relatively large numbers of cells needed for a transplant. The cells must also be all the same to avoid causing other medical problems, such as cancer.

Neurons grown from embryonic stem cells

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 on 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-DA 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 he 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 could 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 could be made from a patient’s adult skin cells in the lab, and then used to make dopamine-producing neurons. In 2010 scientists in the USA treated rats with neurons made from human skin cells using iPS techniques. The transplanted neurons improved features of Parkinson's disease in the rats. However, mice and rats require fewer neurons than humans and it is not yet clear whether this approach would work in patients. More studies are also needed to make sure the cells are safe and would not cause tumours in the brain, and also do not rapidly develop the pathology of Parkinson’s given they are derived from the patients themselves.

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. 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

USA-based researcher Lorenz Studer and his colleagues have recently succeeded in making highly efficient dopamine-producing neurons from human embryonic stem cells and have transplanted them into the brains of rats and mice with a dopamine lesion (to mimic the features seen in Parkinson's disease). The cells did not multiply abnormally and improved some features in the mice. The researchers also transplanted the neurons into monkeys to show that they would survive and function in larger animals. Work is needed before tests can begin on human patients: the neurons need to be made in sufficient numbers to be effective, and produced in a way that ensures the cells are safe and of the right clinical grade. The scientists hope early clinical trials may be able to start in 2017-18.

Malin Parmar and others in Sweden and Italy have taken human skin cells and converted them directly into dopamine-producing neurons. Whether these neurons survive and improve the features of the disease when transplanted into an animal is not yet known. The long-term goal is to make dopamine-producing neurons from patients' own skin or hair cells.

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. Much work still needs to be done before clinical trials can go ahead. For now, the main challenges for scientists are:

  • To identify the type of cells that has the most potential for research and new treatments. So far, researchers have had most success making dopamine-producing neurons from embryonic stem cells, but it is not yet clear whether the lab-grown neurons are close enough to naturally produced nigral neurons to succeed as therapies.
  • To find out how to grow neurons in sufficient quantities and at high enough safety standards to treat patients.
  • 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 and reviewed by Tilo Kunath, Olle LindvallClare Blackburn and Roger Barker.

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.