Is there any future in the use of growth factors to repair the brain in Parkinson’s disease? This is a question I am asked a lot by patients since the publication of the negative GDNF trial earlier this year which was also linked to a 2 part documentary on the BBC. My answer is, yes, but the next trial will need to be thought through very carefully.

The premise behind this approach is that the dying and failing dopaminergic nerve cells (that lie at the heart of what goes wrong in Parkinson’s Disease (PD)) that project from their site of origin in the upper brainstem (substantia nigra) to the striatum can be rescued by giving them a growth factor-if you like a dopamine cell fertiliser. This is not a new idea but became a major focus following the discovery of a new growth factor in 1993, Glial cell line derived neurotrophic factor (GDNF), that seemed very potent at rescuing these cells in the lab. This led in a relatively short time to a series of trials in patients with PD where GDNF was directly infused into the brain. These trials gave mixed results- some showing benefit and others no improvement and so the field remained unsure as to what to do next, if anything. Many concluded that this approach had had its day especially given that the results from similar gene therapy trials using a related GDNF molecule- neurturin – were also not showing signs of obvious benefits to patients.

It was on this background that a new trial of infusing GDNF into the brains of patients with PD was conceived in Bristol by Steve Gill, Alan Whone and colleagues. In this study patients were to be given the growth factor through a new delivery system. Half would get placebo for the first 40 weeks of the trial and half active treatment and then all would get the active treatment for the next 40 weeks. The trial showed that there were no differences between groups using the pre-defined end points of the study, although there were some signals of success using different measures including imaging.

So what should we make of all this? It is clear that just ploughing on doing similar studies is not going to resolve the problems of whether this treatment has a future or should be consigned to history at this point. Those favouring the latter would argue that the growth factor is trying to rescue a system that has already largely died off and that those dopamine cells that are still there are destined to die because of the alpha synuclein pathology within them. In other words, they are not destined to die because they lack a growth factor but because they are being killed from within. Furthermore, it is known that the alpha synuclein pathology of PD can interfere with how GDNF normally works through its receptor. Thus, it is argued, that giving GDNF is not going to work properly because the way it exerts its benefits is blocked by the alpha synuclein pathology.

On the other hand, those advocating that it does have a future would argue that it has not worked that well in trials to date because it was given to patients too late in the disease process; delivered over too small a volume of the diseased brain and then at too low a dose. This coupled to a follow up that was too short with a single arbitrary end point means that the therapy failed for technical reasons not biological ones.

Obviously knowing how to bring these discordant views together is not easy but one way would be to bring all the relevant groups together who work or have worked on this therapy to discuss the issues. This should then led to a decision as to (a) whether a new trial is merited and if so (b) what this should look like in terms of type of patient; dose of GDNF and volume to be given along with the most appropriate end point and when this should be relative to the drug being started. This is what is being planned this August in Grand Rapids in the USA supported by the Cure Parkinson’s Trust.

Indeed, it is only through this collaborative and considered approach that we can hope to advance this therapy and truly discover whether it has a future in PD.

Roger A. Barker has presented at at every World Parkinson Congress since inception. He is a member of the World Parkinson Coalition® Board of Directors and was Chair of the Program Committee for the 5th World Parkinson Congress. He is currently a professor of Clinical Neuroscience at the University of Cambridge and Consultant Neurologist at Addenbrooke’s Hospital in Cambridge, UK.

Ideas and opinions expressed in this post reflect that of the authors solely. They do not reflect the opinions or positions of the World Parkinson Coalition®