Parkinson's Disease and Stem Cells

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Parkinson's disease, caused by the degeneration of dopamine producing cells, may be among the first conditions to be successfully treated using stem cells.

Parkinson’s disease is a condition in which the neuronal message to the muscles is disrupted, resulting in symptoms such as tremors and the impairment of movement and speech. It is caused by the degeneration of dopamine producing cells in an area of the mid region of the brain known as the substantia nigra.

Dopamine is a neurotransmitter – a molecule capable of converting nervous impulses to chemical messages across the synapses, or gaps, between one neurone and the next. It is associated with the control of movement, emotional responses and our ability to experience pleasure and pain.

The Benefits of Stem Cells Compared to Drugs

Various drugs such as Levodopa, Sinemet and the dopamine agonists Requip and Mirapex can either act to initiate more dopamine production or mimic the action of dopamine. However, they ultimately have only limited effectiveness, can cause side effects such as dyskinesias (uncontrolled movements), nausea and confusion and do not reduce the degeneration of the dopamine producing (dopaminergic) nerve cells themselves.

A better and longer lasting treatment would ideally be one where the dopaminergic cells are replaced with healthy ones that can regenerate themselves over the course of the patient’s life. Stem cell therapy, in which differentiated stem cells of embryos or modified adult stem cells, are implanted into the brain, may offer such a solution.

The Current State of Stem Cell Trials

To date, approved scientific trials have only involved the introduction of stem cells to ‘models’ of Parkinson’s disease rather than to human patients themselves. This has usually involved modifying the metabolism of laboratory rats to mimic the symptoms of the disease and then injecting stem cells that have been manipulated into forming dopaminergic cells into the rats.

Researchers at the Michael J. Fox Foundation have found that such trials have been the most successful when embryonic stem cells have been used. It is for this reason that this organization, among others, has campaigned for federal funding for stem cell research since 2001. Although limited funding has been approved over the years, there are still restrictions on the stem cell lines that are available for research purposes.

Induced Pluripotent Stem Cells (iPSCs) and the Future

Fortunately, an alternative to the use of embryonic stem cells was discovered in 2007. Researchers at the University of Wisconsin and the University of Kyoto concurrently found that adult human fibroblast cells, commonly found in connective tissue, could be genetically altered to produce the same proteins as embryonic stem cells. This allowed them to become ‘pluripotent’: in other words, capable of differentiating into a variety of specialized cells, including dopaminergic ones. Other research, involving the reprogramming of neural and testicular cells into pluripotent cells, is also currently underway.

Initially, this modification process involved the introduction of genes to the fibroblast cells via a retrovirus. However, the safety and efficacy of this method have been questioned by scientists at the Whitehead Institute and the Harvard Medical School, who have noted that viral vectors can sometimes affect the differentiation potential of fibroblasts or even cause malignant cell growth.

One solution, they claim, is the use of ‘factor free’ iPSCs – induced fibroblast cells in which the viral reprogramming factors have been removed. This involves the use of an enzyme called Cre-recombinase which helps to rid the iPSCs of potentially harmful transgenes.

Protein Based iPSCs

Alternatively, Sang-Hun Lee, at Hanyang University, Korea, and Kwang-Soo Kim, at Harvard Medical School have developed iPSCs in which the required reprogramming proteins are themselves introduced into fibroblast cells, thus obviating the need for virus delivered transgenes. When these ‘protein based’ iPSCs were implanted into rats modeling Parkinson’s disease the symptoms appeared to be alleviated.

Whether or not any one particular method is more successful than the other, it appears clear that iPSCs are offering new hope and a possible alternative to the ethical issues surrounding the use of embryonic stem cells. Recent tests at the Universities of Göttingen and Tübingen have, moreover, shown that iPSC derived dopaminergic cells can be delivered to rats via nasal sprays rather than by injections. Scientists involved with this research found that the cells became successfully incorporated into the rat brain tissue, surviving and producing dopamine for up to six months.

The Continuing Need for Both Types of Stem Cells

Despite the moderate success of iPSCs, researchers are in agreement that funding for embryonic stem (ES) cell research needs to continue, if only so that the effects of iPSCs can be regularly compared to ES cells in the lab. According to University of Michigan sociologist Owen Smith, 62.1% of current scientific papers on stem cell research involved using both iPS and ES cells together.

At any rate, apart from the complexities of manipulating stem cells to form dopaminergic cells, there are still questions regarding the quality and quantity of dopamine production by these cells if, and when, they are incorporated into Parkinson’s patients. Immune rejection, even of dopaminergic cells derived from the patient’s own body, remains a distinct possibility. In the words of famous Parkinson's sufferer, Michael J. Fox, the struggle for a cure for this disease constantly involves ‘one step forward and two steps back.’

References

•                Euro Stem Cell, 2010, ‘What is Parkinson’s Disease and Can Stem Cells Help?’ eurostemcell.org

•                Journal of Clinical investigation, May 2011, 'Stem Cells May Reverse Parkinson's Disease', Ivanhoe.com

•                Kiessling, A., 2010, ‘The State of the Stem Cell’, bedfordresearch.org

•                Michael J. Fox Foundation for Parkinson's Research, Research Area Position Papers, 2009, ‘Stem Cells 101’, michaeljfox.org

•                Science Daily, 2011, ‘Dramatic Improvement in Parkinson Disease Symptoms Following Intranasal Delivery of Stem Cells to Rat Brains’, sciencedaily.com

•                Soldner et. al, 2009, Whitehead Institute, Harvard Medical School, ‘Parkinson's Disease Patient-Derived Induced Pluripotent Stem Cells Free of Viral Reprogramming Factors’, cell.com