Progress and Prospects in Parkinson's Research/Magazine Section/Cell transplantation

What cell transplantation offers
It has been established that the motor symptoms of Parkinson’s are caused by the death of dopamine producing cells. Current treatments attempt either to make up for the reduced level of dopamine by providing more of it (from levodopa which is converted to dopamine) or to by providing an artificial replacement (agonists). Both of these lose their effectiveness over time and can lead to unpleasant side-effects. The introduction into the brain of new dopamine producing cells offers an alternative. One source is embryonic stem cells derived from foetal material. These have the potential to develop into dopamine producing cells.

This sounds very attractive and is an exciting prospect. However, it is important to note that this is not a cure for Parkinson’s. The latest thinking is that the disease involves a more general degeneration in the neural pathways, perhaps starting in the olfactory bulb region (this is at the bottom of the brain and transmits information from the nose) or in the gut. Patients might recall that they lost their sense of smell years before they became aware of the motor symptoms of Parkinson’s. As the condition progresses non-motor symptoms such as hallucinations, depression or dementia might also appear (although these could be drug-related). In this context it can be seen that simply replacing dopamine may address some of the motor symptoms but is unlikely to halt or reverse the condition altogether. Indeed, there is some evidence that, over time, transplanted cells may also die. This was ascertained from a post-mortem examination of the brains of patients who have died (for unrelated reasons) several years after receiving implants.

Even after setting these reservations to one side it is difficult to see surgical intervention becoming a widespread treatment due to the resources this would require. This is not to be despondent. Transplantation does offer the potential for some patients to enjoy a considerably enhanced quality of life. The procedure can still be cost-effective if there is no longer a need to prescribe expensive cocktails of drugs over a long period. Research is on-going to identify those who will benefit most and the best way to carry out the surgical procedure.

The background
Clinical trials involving the transplantation of foetal stem cells into the brain began as long ago as the late 1980s. The initial results were very promising with some patients being able to come off medication altogether. However, in other cases the impact was minimal and some patients were made much worse, developing severe graft induced dyskinesias that required treatment with deep brain stimulation.

Given the amount of time that has elapsed since then it is perhaps surprising that this approach is still controversial with no consensus as which patients might benefit. In the US the Bush administration imposed, for ideological reasons, an eight year ban on the use of federal funds for research involving the use of embryonic stem cells. This was not overturned until 2009 and undoubtedly slowed progress.

There are a number of reasons why it has proved difficult to draw conclusions from the research that has been carried out so far:


 * There are different ways of delivering the implant – either as solid material or in suspension (as a liquid)
 * Different amounts of implanted material have been used
 * The way in which the implanted material is harvested and stored has not been consistent
 * The exact position in the brain into which the implants are placed and the number of locations has varied
 * It is not clear whether immune suppressants are required to aid the development of the implant
 * Samples have generally been small and with no defined ‘test’ and ‘control’ groups

Given these differences it is not surprising that each trial ends with some uncertainty over what might have happened if it had been conducted differently. Where successful results have been achieved questions have been asked over whether the patients involved genuinely did have Parkinson’s or simply exhibited Parkinsonism. Going forward participants are likely to take the apomorphine challenge to confirm the diagnosis of Parkinson’s.

The effectiveness of a new treatment is generally assessed by means of a double blind test. This involves randomly allocating patients to either test or control group. Those in the test group are given the treatment while the control group receive a placebo. They can then be compared in order to ascertain whether any observed benefits are really due to the treatment (in which case only the test group will show an improvement). In this case the test group receives the implant while the control group undergoes ‘sham surgery’. Participants do not know whether or not they have received the transplant but those in the control group are offered the chance to receive the implant when the research is finished. Where this has been carried out the conclusion was that the transplant made no difference.

This brings into question how success is measured. The UPDRS may be too unwieldy to detect small changes over time. The important thing is that patients should ‘feel better.’ This assessment has been used as a measure of change, but is not really satisfactory because it is entirely subjective. More promising is the use of PET scans. This imaging technique can show the level of dopamine activity in the brain and comparisons made between those who have received implants and the control group.

Current issues
In the US embryonic stem cell research has slipped down the research agenda. In a webcast to outline research priorities for 2013 Tod Sherer, the Chief Executive Officer of the Fox Foundation, stated that, while the Foundation is still supporting research in this area, it is not the primary focus.

In Europe the TRANSEURO project aims to determine once and for all whether the use of foetal stem cells is effective in restoring dopamine production in the brain. This is a large collaborative project funded by the EU’s Seventh Framework, and carried out by research teams in the UK, Sweden, Germany, France and Austria. The researchers have analysed the results of previous experiments and concluded that:


 * Early stage patients are most likely to benefit from the procedure. For those in the later stages the dopaminergic pathways may have been irreparably damaged.
 * Some of the more negative results, such as graft induced dyskinesias only occur if the patient was suffering from these symptoms already.
 * Advances in surgical techniques and methods of storing and transporting foetal material have increased the chances that the procedure will be effective.
 * The use of immunosuppressant drugs will increase the chance that implanted material will develop as expected.

The project involves the recruitment of a large sample of people with Parkinson’s who have had the condition for less than ten years. Participants attend every six months to undergo a series of tests to measure motor and cognitive functions. Suitable patients will be selected from this larger group to take part in the next stage. TRANSEURO is not a double blind experiment but the intention is to investigate, using PET scans, how the symptoms of Parkinson’s progress in those who have had the procedure compared with a matched sample who have not. The first transplants were due to take place in Sweden early in 2013.

The future
Foetal stem cells are not the only material that may be suitable for transplantation. In 2007 a research team in Japan discovered a way to change skin cells into embryonic stem cells. These are known as induced pluripotent stem cells (IPS). With this approach the technical and moral issues associated with the use of foetal material go away, as do issues with rejection of the implant. As always turning theory into practice is not as straightforward as it might appear. Cells taken from other parts of the body may not behave in exactly the same way as the original cells. Research in this area is continuing and the latest advance is to turn cells of one type directly in to another without going through the embryonic stage. This may overcome problems associated with the way IPS cells develop after they have been transplanted.

Another candidate for transplantation are so-called growth factors, of which the best known is glial cell-derived neurotrophic factor (GDNF). Discovered in 1991, GDNF is a protein that has been shown to protect, nurture and restore many different types of cell, including those that produce dopamine. This has been demonstrated in animal models. Taken at face value this is the closest to a cure that we have come, at least in theory. Several challenges have emerged:


 * GDNF is not a single entity, it is part of a family of so-called trophic agents and it is not clear exactly which ‘type’ will be the most effective.
 * How GDNF might be delivered to patients. Possible solutions include surgery, a catheter inserted into the brain or the uses of viruses to deliver genetic changes.
 * Perhaps most importantly there are still risks with some experiments showing that side effects can be made worse.

There is also the possibility to deliver growth factors along with pluripotent cells. It is possible that the two might, in combination, produce a means to halting and then reversing the development of Parkinson’s.

Conclusion
For people with Parkinson’s the journey outlined here can be seen as a source of great optimism, as well as some frustration. An effective treatment for Parkinson’s that goes beyond the relief of symptoms always seems to be tantalisingly close. Theoretical models and early experiments are positive, then there are setbacks that cause new research to stall and a general feeling of uncertainty prevails. As researchers pluck up the courage to try again other approaches have come to the fore. This is, perhaps, a plea for greater collaboration. In this respect the TRANSEURO project is to be applauded in that the leading research institutes in this field in Europe are all involved and we will finally know the true potential for the use of embryonic stem cells as a treatment for Parkinson’s.

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