Parkinson's Disease is a chronic and progressive disease of the central nervous system (CNS) which involves the loss of nerve cells residing in the brain that produce a chemical called dopamine.

Maladie de Parkinson

Parkinson’s Disease is a chronic and progressive disease of the central nervous system (CNS) which involves the loss of nerve cells residing in the brain that produce a chemical called dopamine.

Dopamine, a neurotransmitter, allows messages to be transmitted from the substantia nigra, the part of the brain that helps control and coordinate movement to the muscles. The symptoms of Parkinson’s appear when about 80 per cent of the dopamine-producing cells are lost. For this reason, people are usually not diagnosed until after age 55.

About 4 million people worldwide have Parkinson’s Disease, making it one of the most common neurodegenerative diseases. Its cause is unknown although there appear to be a number of genes involved. Other contributing factors (or theories) include exposure to environmental toxins, inflammation, build up of protein inside the cells, oxidative stress, viral infection and changes to the DNA.

While the cause remains a mystery, and while symptoms, patterns of progression and responsiveness to treatment are variable, scientists have known for some time that a lack of dopamine is responsible for the disease.

Symptoms and treatments

Parkinson's causes loss of control over voluntary and involuntary muscles, and eventually problems with memory, concentration, mood and cognitive functions as well. The clinical signs are an uncontrollable tremor in the hands, feet or face, rigidity, slowness of movement (bradykinesia), difficulty initiating movement and increasing problems with balance, gait and posture. Swallowing, bowel and bladder function, as well as automatic functions of the body such as pulse and blood pressure, can also be affected.

Because the reason for these symptoms is very straightforward (lack of dopamine), treatment has traditionally focused on replacing dopamine through drugs, notably levadopa. This drug is converted to dopamine in the body while other drugs mimic dopamine, although not consistently and not without side effects. Other treatments try to prevent the death (or slow down the demise) of the brain's own dopamine-producing cells (neuroprotection) or to stimulate deep brain regions with electrical impulse to control symptoms.

Haut de la page

Can stem cells help?

While most clinical trials have focused on improved drug therapies, basic research has focused on why these particular neurons die in the first place and on finding ways to regenerate, repair or replace these cells so functioning can be restored (neurogenesis).

Stem cell therapy for Parkinson’s
Stem cell therapy is very promising because this disease is clearly related to the failure of one specific kind of cell to do its job. It has been proven in both animal models and clinical practice that when dopamine is reintroduced into the central nervous system, the symptoms abate or are reversed. Thus, if stem cells can be coaxed to become dopamine-producing neurons, either before or after transplantation deep inside the brain, full recovery of lost functioning is theoretically possible.

This has been achieved with limited success in clinical trials over the last 15 years by transplanting fetal stem cells into the brains of patients with Parkinson’s disease. Using imaging technology called PET scanning, researchers were able to see that the transplanted neurons grew and made functional connections, somewhat reducing the severity of symptoms, although results were variable.

As the clinical research protocols are being progressively refined, scientists are increasingly certain of the principle that stem cells can be successfully transplanted, survive and produce dopamine with expected improvements in motor control and coordination.

Finding a supply source

Clinical trials using fetal cell transplantation have now been conducted in about 400 patients worldwide, but using fetal tissue is not a good long-term source of renewable cells, for ethical as well as practical reasons. Now, the major goal of investigators is to generate a source of cells that can be grown in large supply, maintained indefinitely in the laboratory, and differentiated efficiently into dopamine-producing neurons that work when transplanted into Parkinson’s patients.

This goal has motivated scientists to study both embryonic and adult stem cells as alternative sources of dopamine-producing neurons. In laboratories, with the right combination of growth factors, undifferentiated stem cells can be cultivated to a point where they are committed to becoming dopamine neurons. These are then implanted to finish maturing in the brain.

Embryonic cells appear to differentiate into neurons in a more straightforward manner than many other cell types. However, in animal models they appear to carry the risk of developing cancerous tumors. We don’t yet know if adult neural stem cells have the same potential as embryonic stem cells or carry a similar risk.

There are still many unanswered questions. Among those currently being researched are: which stem cells (e.g. embryonic, blood, bone marrow, retina, skin cells) are best for treating Parkinson’s; tracking cell markers to learn which cells survive, multiply and successfully produce dopamine under what conditions; determining the cues that neural stem cells use to differentiate into dopamine-producing cells; decoding signals in the brain environment that allow transplanted cells to survive, integrate and function properly; and, deciding which areas of the brain and whether transplantation or some other method of delivery (e.g. using genes) would yield the best results.

Finding the switch

An alternative to transplantation is mobilizing the brain to reverse the depletion of dopamine-producing nerve cells. Scientists are investigating how the brain turns on its own mechanism for self-repair, possibly involving adult stem cells that reside in certain parts of the brain. The brain’s white matter contains multipotent progenitor cells that can multiply and form all the major cell types of the brain, including neurons. These appear to be remnants of stem cells that existed during fetal brain development that might be coaxed into becoming dopamine-producing cells in a patient suffering from Parkinson’s disease.

This capacity to regenerate relies on growth hormones (neurotrophic factors such as GNDF) and other signaling molecules that help cells survive and grow. Scientists are beginning to understand what fires up a patient’s own stem cells and internal repair mechanism to allow the body to cope with damage from disease or injury. Even transplanted neural cells have a “homing instinct” that leads them to gravitate to exactly that part of the brain that is injured and needs regeneration.

Haut de la page


Looking to the future

Research continues in Canada, the US, the UK, Israel, Sweden, Israel and Japan on using stem cells to treat Parkinson’s Disease. This involves stem cells from rodents, monkeys, pigs and human embryos, with varying results. At the same time, the capacity of the brain to repair itself under the right conditions is increasingly evident. Therefore, there may be more than one avenue to treatment that relies on stem cell research.

Translating success (and failure) from animal models to human trials requires controlling for multiple parameters, particularly the source and type of stem cell used, the culture in which they are grown, the protocol for injecting them into the brain, the method of activating cell differentiation, and what factors ensure their survival.

Unfortunately, in recent experiments, tumors appeared as a result of transplanting embryonic stem cells, indicating that alongside potential benefits of stem cell therapy, there are also risks.

Another risk became evident in 2008 when the idea of treating Parkinson’s with stem cells had a setback because an autopsy on a stem cell recipient found that there were signs of Parkinson’s in transplanted cells. That means that the disease is able to spread inside the brain from a patient’s own cells to the transplanted ones.

Nevertheless, imaging technology (for tracking how cells behave within the brain) and bioengineering (for creating a large supply of cells for therapeutic use) make the prospect of using stem cells to treat Parkinson’s increasingly likely. Further clinical trials can be expected as the characteristics of neural stem cells are better understood by basic scientists and various strategies for replicating and differentiating stem cells in vitro and in vivo are tested.

Progressing to the next step requires a multi-disciplinary network of scientists, clinicians and laboratories in order to arrive at a safe and effective protocol for transplanting stem cells into the brain.

If such therapeutic strategies are successful, they may be applied to the treatment of stroke, spinal cord injury, cancer and other degenerative diseases where cell replacement and regeneration would restore normal function of the nervous system.


Haut de la page


Canada


Over 100,000 people suffer from Parkinson’s Disease in Canada, and Canada is at the forefront of stem cell research for this disease.

Research teams at the Universities of Calgary and Toronto and at the Brain Repair Centre at Dalhousie University are working to overcome major challenges for using stem cells to treat Parkinson’s Disease.

The first step is transforming human embryonic stem cells into cells that produce dopamine. Integrating these cells into the brain to regenerate the circuitry that controls movement requires two other critical steps: being able to produce an unlimited quantity of such cells in a controlled and standardized fashion to guarantee reliable results, and using a safe and effective protocol for transplantation. Research is ongoing to accomplish these aims.

The Halifax Protocol

To date, one of the most important Canadian contributions to international research is the Halifax Protocol for injecting cells safely into the human brain. Now recognized by neurosurgeons as the international standard for safe and effective brain repair using cell implantation, this protocol will make the clinical application of stem cell research for Parkinson’s disease possible in the future.

Canadian researchers are also pioneers in devoting significant attention to the ethical considerations in treating Parkinson’s disease through stem cell implantation. They wish to encourage this debate in tandem with laboratory research in anticipation of clinical trials.

Haut de la page

 

Other resources

General Information

Parkinson's Society of Canada
National Parkinson's Foundation
European Parkinson's Disease Association
Parkinson's Disease Society
Michael J. Fox Foundation

Stem Cells and Parkinson's

ISSCR Website
CIRM video

 

Research

Stem Cell Network
Parkinson Society Canada

The Halifax Protocol

www.brainrepair.ca
www.neuraltransplantation.dal.ca

United States

National Institutes of Health (2006 report)
National Institute of Neurological Disorders
National Parkinson Foundation


Clinical Trials

www.pdtrials.org/front/
www.parkinson.org/site/pp.asp?c=9dJFJLPwB&b=71404
www.clinicaltrials.gov

United Kingdom

Parkinson’s Disease Society

Articles of Interest

NIH update on Research Agenda for Parkinson’s, July 2008 (US)
www.stemcellnetwork.ca/news/articles/pho?id=169 (Canada)
newsvote.bbc.co.uk/mpapps/pagetools/print/news.bbc.co.uk/1/hi/health/3853791.stm (Israel)
newsvote.bbc.co.uk/mpps/pagetools/print/news.bbc.co.uk/1/hi/health/4134343.stm (Japan)


Glossary

bioengineering

Technology dedicated to manufacturing a large supply of stem cells for therapeutic use.

dopamine
A neurotransmitter that allows messages to be transmitted from the brain to the muscles.

fetal stem cells
Fetal stem cells are retrieved from tissue that is removed from a fetus electively aborted seven to nine weeks after conception.

Halifax Protocol
This protocol, developed at the Brain Repair Center at Dalhousie University is now recognized as the international standard for safe and effective brain repair using cell implantation.

human neuronal stem cells (hNSC)

Stem cells derived from fetal brain tissue.

imaging technology
PET scanning and other advanced imaging techniques help scientists track how cells behave within the body.

in vitro
Experimentation in a laboratory culture or petri dish, rather than in a living organism.

in vivo
Experimentation done on living tissue rather than in a controlled environment. Both clinical trials and animal research are forms of in vivo research.

progenitor cell
Progenitor cells derive from stem cells and are pluripotent. They give rise to many different kinds of cells.

neurotrophic factors
Chemicals that are similar to hormones that stimulate differentiation of stem cells when added to the laboratory culture, also sometimes called growth factors.

self-repair
The ability of an organ to repair damaged tissue or lost cells using its own adult stem cells. Some tissue, like muscle, bone, skin and blood is routinely repaired or regenerated in this way.

substantia nigra
The part of the brain that helps control and coordinate movement to the muscles and is affected by Parkinson’s disease.

Haut de la page