The Trials and Tribulation of Cell Transplants for Parkinson's Disease!
The use of cell based therapies for Parkinson’s disease (PD) has a long history going back to the late 1970s and 1980s when it was shown by the pioneering team of Anders Björklund in Lund, Sweden that developing dopamine cells from the developing fetal rat brain could survive being grafted into the brain of adult rats. This not only showed that such cells could survive transplantation but that they could make connections with the host brain and restore back to normal the behavioral deficits seen in animals that had had lesions of their dopamine system. Lesions that were used to mimic the core problem in PD.
These pioneering studies were then replicated in other labs around the world and by the end of the 1980s, it was felt that the time was right to try it in patients with PD. Over the next 10 years this group led by the neurologist Olle Lindvall in Lund, Sweden oversaw the grafting of 17 patients with moderately advanced PD. This open label trial (meaning that both patient and clinician knew they were treating the patient with this transplanted material- i.e. no placebo arm) evolved in terms of how the patients were treated over time, as the team sought to best deliver such a therapy optimally. This involved trying to work out: how much fetal material should be grafted to ensure enough dopamine cells survived in the PD brain; at what exact sites within the brain and in which particular type of PD patient. This work reported that in some patients the transplants worked fabulously well, with patients able to come off all their anti-PD medication for years, while in others the results were less dramatic and in some cases no response at all was seen post grafting. Thus by the turn of the 20th century, the community working on this approach in Europe were seeking to be improve on these variable results. However, the field was suddenly embroiled in controversy following the publication of two high profile trials in the USA.
These trials that started in the early 1990s sought to test whether this approach using human fetal dopamine cells really did work, as there were questions as to whether the benefits reported by the Swedish and other groups were simply placebo effects. Thus the major funding agency in the USA, the National Institutes of Health (NIH), supported two double blind sham surgery trials (i.e. a trial in which neither the patient nor the examining clinician know whether the patient has had a transplant or simply pretend surgery) to see whether this tissue could really repair the brain in PD and improve patients. These two trials were thus planned and prosecuted at a time when the Swedish team were still trying to work out how to do this optimally- which may also explain why the two US studies were so different in terms of their whole approach (amount of fetal tissue grafted; type of patient; mode of tissue engraftment; level of immune suppression post grafting; time of follow up to see an effect etc).
These two NIH funded trials published their results in 2001 and 2003 and reported that these types of transplants did not really work and in fact caused side effects in significant numbers of patients with the development of involuntary movements (dyskinesias) that were driven by the transplant itself (graft induced dyskinesias). A result that left the field was on the verge of being abandoned, especially as other better treatments now were available for patients with advancing PD such as deep brain stimulation.
However a team in Europe, led by Roger Barker, sought to re-evaluate the clinical data from all these trials to see whether there was any merit in persevering with this whole approach. This seemed critical given that some patients had done remarkably well clinically with normalization of dopamine levels in their brain on scans and at post mortem, and that stem cell derived dopamine cells were fast being developed in the laboratory for clinical translation.
This work revealed that dopamine neuronal cell replacement therapies may have merit if more attention was paid to patient selection, tissue preparation and implantation, immunosuppression and trial design. This led to a new EU funded trial called TRANSEURO which is currently ongoing and that will hopefully be able to announce its results in 2020, 3 years after the last patient has been grafted.
This trial has not only re-established cell therapies as a viable option for treating the dopaminergic aspects of PD, but has helped us work out how to do this more rationally in the clinic as we now begin to face the very real prospect of first in human stem cell derived dopamine cell transplants in PD. These stem cell derived product will either use embryonic stem cells (ES cells) which are derived from spare embryos from IVF programmes, or induced pluripotential stem cells (iPSC) which are ES like cells derived from reprogrammed adult human cells. In both cases, a number of teams have managed to engineer these cells into dopamine cells of the type that are lost in PD and which work as well as the original human fetal dopamine cells in the very same animal models that were used by the Björklund team back in the early 1980s. Thus all that currently lies between the use of these cells and first in human trials is the necessary safety testing and clinical manufacture of them as is rightly required by the regulatory authorities.
Of course this is not to say that there are no stem cell trials ongoing in PD right now, but these are often using cells that have not been adequately tested in the lab prior to being moved into patients. As such these cells at best will make no difference, at worse they may cause tumours and kill patients. In addition, these unlicensed therapies are also subject to big price tags for families and patients with PD, which cannot be justified given this whole approach is still experimental and thus needs to be done through properly funded and independently peer reviewed trials.
Thus cell therapies in 2017 are an exciting prospect in the future treatment of PD, as long as the trials are done properly and not ambushed by commercial greed! However, while exciting, they are not cures as all they will ever do is repair and replace the lost dopaminergic network- a network which we know can be transformative to patients given what we have been witnessing for the last 50 years with L-dopa and similar drugs. However, unlike L-dopa these transplants should avoid the long term complications and by so doing have the potential to transform the natural history of treated PD.
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Roger A. Barker, PhD, MRCP is a member of the World Parkinson Coalition® Board of Directors and has spoken at every WPC since inception. He is also the Program Chair for 5th World Parkinson Congress. He is currently a professor in the Department of Clinical Neuroscience at the University of Cambridge in Cambridge, UK.
Ideas and opinions expressed in this post reflect that of the author solely. They do not reflect the opinions or positions of the World Parkinson Coalition®.