Parkinson’s is a neurodegenerative condition. This means that cells in the brain are being lost over time. Any ‘cure’ for Parkinson’s is going to require some form of cell replacement therapy – introducing new cells that can replace those that were lost.
Cell transplantation represents one approach to cell replacement therapy, and this week we learned that the Japanese regulatory authorities have given the green light for a new cell transplantation clinical trial to take place in Kyoto.
This new trial will involve cells derived from induced pluripotent stem cells (or IPS cells).
In today’s post we will discuss what induced pluripotent stem cells are, what previous research has been conducted on these cells, and what we know about the new trial.
Source: Glastone Institute
The man in the image above is Prof Shinya Yamanaka.
He’s a rockstar in the biomedical research community.
Prof Yamanaka is the director of Center for induced Pluripotent Stem Cell Research and Application (CiRA); and a professor at the Institute for Frontier Medical Sciences at Kyoto University.
But more importantly, in 2006 he published a research report that would quite literally ‘change everything’.
In that report, he demonstrated a method by which someone could take a simple skin cell (called a fibroblast), grow it in cell culture for a while, and then re-program it so that it would transform into a stem cell – a cell that is capable of becoming any kind of cell in the body.
The transformed cells were called induced pluripotent stem (IPS) cell – ‘pluripotent’ meaning capable of any fate.
It was an amazing feat that made the hypothetical idea of ‘personalised medicine’ suddenly very possible – take skin cells from anyone with a particular medical condition, turn them into whatever cell type you like, and then either test drugs on those cells or transplant them back into their body (replacing the cells that have been lost due to the medical condition).
Personalised medicine with IPS cells. Source: Bodyhacks
IPS cells are now being used all over the world, for all kinds of biomedical research. And many research groups are rushing to bring IPS cell-based therapies to the clinic in the hope of providing the long sort-after dream of personalised medicine.
This week the Parkinson’s community received word that the Japanese regulatory authorities have agreed for researchers at Kyoto University to conduct a cell transplantation trial for Parkinson’s, using dopamine neurons derived from IPS cells. And the researchers are planning to begin their study in the next month.
In today’s post we are going to discuss this exciting development, but we should probably start at the beginning with the obvious question:
What exactly is an IPS cell?
Chinese researchers recently published pre-clinical research demonstrating the use of their protocol for generating stem cell-derived neurons for cell transplantation in Parkinson’s.
The data represents the last step/proof-of-principle stage for taking this procedure into clinical trials (which are ongoing).
In today’s post, we will discuss what cell transplantation is, we will review the new data, and we will consider some of the issues associated with taking this procedure to the clinic.
Brain surgery. Source Bionews-tx
As we have discussed before, any ‘cure’ for Parkinson’s requires 3 components:
- A disease halting mechanism – slowing or stopping the progression of the condition
- A neuroprotective agent – a treatment that will protect and support the remaining cells
- Some form of cell replacement therapy – introducing new cells to replace the ones that have been lost
Now, the bad new is that there is no ‘silver bullet’ on the horizon that provides all three (for example, there is no neuroprotective agent that also replaces lost cells).
But the good news is that we have a great deal of clinical research being conducted in all three of these areas. This video provides an overview of just some of the many different ways we are approaching all three components:
Recently a research report focused on a cell transplantation (a form of cell replacement therapy) approach for Parkinson’s was published by a group of researchers in China. They have proposed that the results presented in the report justify their efforts to take this approach forward into clinical testing.
What is cell transplantation?
The great ice hockey player Wayne Gretzky once said “A good hockey player plays where the puck is. A great hockey player plays where the puck is going to be” (the original quote actually came from his father, Walter).
At the start of each year, it is a useful practise to layout what is planned for the next 12 months. This can help us better anticipate where ‘the puck’ will be, and allow us to prepare for things further ahead.
2017 was an incredible year for Parkinson’s research, and there is a lot already in place to suggest that 2018 is going to be just as good (if not better).
In this post, we will lay out what we can expect over the next 12 months with regards to the Parkinson’s-related clinical trials research of new therapies.
Charlie Munger (left) and Warren Buffett. Source: Youtube
Many readers will be familiar with the name Warren Buffett.
The charming, folksy “Oracle of Omaha” is one of the wealthiest men in the world. And he is well known for his witticisms about investing, business and life in general.
Warren Buffett. Source: Quickmeme
He regularly provides great one liners like:
“We look for three things [in good business leaders]: intelligence, energy, and integrity. If they don’t have the latter, then you should hope they don’t have the first two either. If someone doesn’t have integrity, then you want them to be dumb and lazy”
“Work for an organisation of people you admire, because it will turn you on. I always worry about people who say, ‘I’m going to do this for ten years; and if I really don’t like it very much, then I’ll do something else….’ That’s a little like saving up sex for your old age. Not a very good idea”
“Choosing your heroes is very important. Associate well, marry up and hope you find someone who doesn’t mind marrying down. It was a huge help to me”
Mr Buffett is wise and a very likeable chap.
Few people, however, are familiar with his business partner, Charlie Munger. And Charlie is my favourite of the pair.
Recently I was invited to speak at the 6th Annual East Midlands Parkinson’s Research Support Network meeting at the Link Hotel, in Loughborough. The group is organised and run by the local Parkinson’s community and supported by Parkinson’s UK. It was a fantastic event and I was very grateful to the organisers for the invitation.
They kindly gave me two sessions (20 minutes each) which I divided into two talks: “Where we are now with Parkinson’s research?” and “Where we are going with Parkinson’s research?”. Since giving the talk, I have been asked by several attendees if I could make the slides available.
The slides from the first talk can be found by clicking here.
I have also made a video of the first talk with a commentary that I added afterwards. But be warned: my delivery of this second version of the talk is a bit dry. Apologies. It has none of my usual dynamic charm or energetic charisma. Who knew that talking into a dictaphone could leave one sounding so flat.
Anyways, here is the talk – enjoy!
I hope you find it interesting. When I have time I’ll post the second talk.
We have been contacted by some readers asking about a new stem cell transplantation clinical trial for Parkinson’s disease about to start in China (see the Nature journal editorial regarding this new trial by clicking here).
While this is an exciting development, there have been some concerns raised in the research community regarding this trial.
In today’s post, we will discuss what is planned and what it will mean for stem cell transplantation research.
Brain surgery. Source Bionews-tx
Parkinson’s disease is a progressive neurodegenerative condition.
This means that cells in the brain are slowly being lost over time. What makes the condition particularly interesting is that certain types of brain cells are more affected than others. The classic example of this is the dopamine neurons in an area of the brain called the substantia nigra, which resides in the midbrain.
The number of dark pigmented dopamine cells in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source: Adapted from Memorangapp
Approximately 50% of the dopamine neurons in the midbrain have been lost by the time a person is diagnosed with Parkinson’s disease (note the lack of dark colouration in the substantia nigra of the Parkinsonian brain in the image above), and as the condition progresses the motor features – associated with the loss of dopamine neurons – gradually get worse. This is why dopamine replacement treatments (like L-dopa) are used for controlling the motor symptoms of Parkinson’s disease.
A lot of research effort is being spent on finding disease slowing/halting treatments, but these will leave many people who have already been diagnosed with Parkinson’s disease still dealing with the condition. What those individuals will require is a therapy that will be able to replace the lost cells (particularly the dopamine neurons). And researchers are also spending a great deal of time and effort on findings ways to do this. One of the most viable approaches at present is cell transplantation therapy. This approach involves actually injecting cells back into the brain to adopt the functions of the lost cells.
How does cell transplantation work?
We have discussed the history of cell transplantation in a previous post (Click here to read that post), and today we are simply going to focus on the ways this experimental treatment is being taken forward in the clinic.
Many different types of cells have been tested in cell transplantation experiments for Parkinson’s disease (Click here for a review of this topic), but to date the cells that have given the best results have been those dissected from the developing midbrain of aborted embryos.
This now old fashioned approach to cell transplantation involved dissecting out the region of the developing dopamine neurons from a donor embryo, breaking up the tissue into small pieces that could be passed through a tiny syringe, and then injecting those cells into the brain of a person with Parkinson’s disease.
The old cell transplantation process for Parkinson’s disease. Source: The Lancet
Critically, the people receiving this sort of transplant would require ‘immunosuppression treatment’ for long periods of time after the surgery. This additional treatment involves taking drugs that suppress the immune system’s ability to defend the body from foreign agents. This step is necessary, however, in order to stop the body’s immune system from attacking the transplanted cells (which would not be considered ‘self’ by the immune system), allowing those cells to have time to mature, integrate into the brain and produce dopamine.
The transplanted cells are injected into an area of the brain called the putamen. This is one of the main regions of the brain where the dopamine neurons of the substantia nigra release their dopamine. The image below demonstrates the loss of dopamine (the dark staining) over time as a result of Parkinson’s disease (PD):
The loss of dopamine in the putamen as Parkinson’s disease progresses. Source: Brain
In cell transplant procedures for Parkinson’s disease, multiple injections are usually made in the putamen, allowing for deposits in different areas of the structure. These multiple sites allow for the transplanted cells to produce dopamine in the entire extent of the putamen. And ideally, the cells should remain localised to the putamen, so that they are not producing dopamine in areas of the brain where it is not desired (possibly leading to side effects).
Targeting transplants into the putamen. Source: Intechopen
Postmortem analysis – of the brains of individuals who have previously received transplants of dopamine neurons and then subsequently died from natural causes – has revealed that the transplanted cells can survive the surgical procedure and integrate into the host brain. In the image below, you can see rich brown areas of the putamen in panel A. These brown areas are the dopamine producing cells (stained in brown). A magnified image of individual dopamine producing neurons can be seen in panel B:
Transplanted dopamine neurons. Source: Sciencedirect
The transplanted cells take several years to develop into mature neurons after the transplantation surgery, and the benefits of the transplantation technique may not be apparent for some time (2-3 years on average). Once mature, however, it has also been demonstrated (using brain imaging techniques) that these transplanted cells can produce dopamine. As you can see in the images below, there is less dopamine being processed (indicated in red) in the putamen of the Parkinsonian brain on the left than the brain on the right (several years after bi-lateral – both sides of the brain – transplants):
Brain imaging of dopamine processing before and after transplantation. Source: NIH
Sounds like a great therapy for Parkinson’s disease right?
So why aren’t we doing it???
1. The tissue used in the old approach for cell transplantation in Parkinson’s disease was dissected from embryonic brains. Obviously there are serious ethical and moral problems with using this kind of tissue. There is also a difficult problem of supply: tissue from at least 3 embryos is required for transplanting each side of the brain (6 embryos in total). Given these issues, researchers have focused their attention on a less controversial and more abundant supply of cells: brain cells derived from embryonic stem cells (the new approach to cell transplantation).
Human embryonic stem cells. Source: Wikipedia
2. The second reason why cell transplantation is not more widely available is that in the mid 1990’s, the US National Institutes of Health (NIH) provided funding for the two placebo-controlled, double blind studies to be conducted to test the efficacy of the approach. Unfortunately, both studies failed to demonstrate any beneficial effects on Parkinson’s disease features.
In addition, many (15% – 50%) of transplanted subjects developed what are called ‘graft-induced dyskinesias’. This involves the subjects display uncontrollable/erratic movement (or dyskinesias) as a result of the transplanted cells. Interestingly, patients under 60 years of age did show signs of improvement on when assessed both clinically (using the UPDRS-III) and when assessed using brain imaging techniques (increased F-dopa uptake on PET).
Both of the NIH trials have been criticised by experts in the field for various procedural failings that could have contributed to the failures. But the overall negative results left a dark shadow over the technique for the better part of a decade. Researchers struggled to get funding for their research.
And this is the reason why many researchers are now urging caution with any new attempts at cell transplantation clinical trials in Parkinson’s disease – any further failures will really harm the field, if not kill if off completely.
Are there any clinical trials for cell transplantation in Parkinson’s disease currently being conducted?
Yes, there are currently two:
Firstly there is the Transeuro being conducted in Europe.
The Transeuro trial. Source: Transeuro
The Transeuro trial is an open label study, involving 40 subjects, transplanted in different sites across Europe. They will receive immunosuppression for at least 12 months post surgery, and the end point of the study will be 3 years post surgery, with success being based on brain imaging of dopamine release from the transplanted cells (PET scans). Based on the results of the previous NIH funding double blind clinical studies discussed above, only subject under 65 years of age have been enrolled in the study.
The European consortium behind the Transeuro trial. Source: Transeuro
In addition to testing the efficacy of the cell transplantation approach for Parkinson’s disease, another goal of the Transeuro trial is to optimise the surgical procedures with the aim of ultimately shifting over to an embryonic stem cells oriented technique in the near future with the proposed G-Force embryonic stem cell trials planned for 2018 (the Transeuro is testing the old approach to cell transplantation).
The second clinical study of cell transplantation for Parkinson’s disease is being conducted in Melbourne (Australia), by an American company called International Stem Cell Corporation.
This study is taking the new approach to cell transplantation, but the company is using a different type of stem cell to produce dopamine neurons in the Parkinsonian brain.
Specifically, the researchers will be transplanting human parthenogenetic stem cells-derived neural stem cells (hpNSC). These hpNSCs come from an unfertilized egg – that is to say, no sperm cell is involved. The female egg cell is chemically encouraged to start dividing and then it becoming a collection of cells that is called a blastocyst, which ultimately go on to contain embryonic stem cell-like cells.
The process of attaining embryonic stem cells. Source: Howstuffworks
This process is called ‘Parthenogenesis’, and it’s not actually as crazy as it sounds as it occurs naturally in some plants and animals (Click here to read more about this). Proponents of the parthenogenic approach suggest that this is a more ethical way of generating ES cells as it does not result in the destruction of a viable organism.
Regular readers of this blog will be aware that we are extremely concerned about this particular trial (Click here and here to read previous posts about this). Specifically, we worry that there is limited preclinical data from the company supporting the efficacy of these hpNSC cells being used in the clinical study (for example, researchers from the company report that the hpNSC cells they inject spread well beyond the region of interest in the company’s own published preclinical research – not an appropriate property for any cells being taken to the clinic). We have also expressed concerns regarding the researchers leading the study making completely inappropriate disclosures about the study while the study is ongoing (Click here to read more about this). Such comments only serve the interests of the company behind the study. And this last concern has been raised again with a quote in the Nature editorial about the Chinese trial:
“Russell Kern, chief scientific officer of the International Stem Cell Corporation in Carlsbad, California, which is providing the cells for and managing the Australian trial, says that in preclinical work, 97% of them became dopamine-releasing cells” (Source)
We are unaware of any preclinical data produced by Dr Kern and International Stem Cell Corporation…or ANY other research lab in the world that has achieved 97% dopamine-releasing cells. We (and others) would be interested in learning more about Dr Kerns amazing claim.
The International Stem Cell Corporation clinical trial is ongoing. For more details about this second ongoing clinical trial, please click here.
So what do we know about the new clinical study?
The clinical trial (Titled: A Phase I/II, Open-Label Study to Assess the Safety and Efficacy of Striatum Transplantation of Human Embryonic Stem Cells-derived Neural Precursor Cells in Patients With Parkinson’s Disease) will take place at the First Affiliated Hospital of Zhengzhou University in Henan province.
The researchers are planning to inject neuronal-precursor cells derived from embryonic stem cell into the brains of individuals with Parkinson’s disease. They have 10 subjects that they have found to be well matched to the cells that they will be injecting, which will help to limit the chance of the cells being rejected by the body.
- Incidence of treatment-emergent adverse events, as assessed by brain imaging and blood examination at 6 months post transplant.
Number of subjects with adverse events (such as the evidence of transplant failure or rejection)
In addition to these, there will also be a series of secondary outcome measures, which will include:
- Change in Unified Parkinson’s Disease Rating Scale (UPDRS) score at 12 months post surgery, when compared to baseline scores. Each subject was independently rated by two observers at each study visit and a mean score was calculated for analysis.
- Change in DATscan brain imaging at 12 months when compared to a baseline brain scan taken before surgery. DATscan imaging provides an indication of dopamine processing.
- Change in Hoehn and Yahr Stage at 12 months, compared to baseline scores. The Hoehn and Yahr scale is a commonly used system for Parkinson’s disease.
The trial will be a single group, non-randomized analysis of the safety and efficacy of the cells. The estimated date of completion is December 2020.
Why are some researchers concerned about the study?
Professor Qi Zhou, a stem-cell specialist at the Chinese Academy of Sciences Institute of Zoology will be leading the study and he has a REALLY impressive track record in the field of stem cell biology. His team undertaking this study have a great deal of experience working with embryonic stem cells, having published some extremely impressive research on this topic. But, (and it’s a big but) they have published a limited amount of research in peer-reviewed journals on cell transplantation in models of Parkinson’s disease. Lorenz Studer is one of the leading scientists in this field, was quoted in an editorial in the journal Nature this week:
“Lorenz Studer, a stem-cell biologist at the Memorial Sloan Kettering Cancer Center in New York City who has spent years characterizing such neurons ahead of his own planned clinical trials, says that “support is not very strong” for the use of precursor cells. “I am somewhat surprised and concerned, as I have not seen any peer-reviewed preclinical data on this approach,” he says.” (Source)
In addition to the lack of published research by the team undertaking the trial, the research community is also worried about the type of cells that are going to be transplanted in this clinical trial. Most of the research groups heading towards clinical trials in this area are all pushing embryonic stem cells towards a semi-differentiated state. That is, they are working on recipes that help the embryonic stem cells grow to the point that they have almost become dopamine neurons. Prof Zhou and his colleagues, however, are planning to transplant a much less differentiated type of cell called a neural-precursor cell in their transplants.
Neuronal-precursor cells. Source: Wired
Neuronal-precursors are very early stage brain cells. They are most likely being used in the study because they will survive the transplantation procedure better than a more mature neurons which would be more sensitive to the process – thus hopefully increasing the yield of surviving cells. But we are not sure how the investigators are planning to orient the cells towards becoming dopamine neurons at such an early stage of their development. Neuronal-precursors could basically become any kind of brain cell. How are the researchers committing them to become dopamine neurons?
Are these concerns justified?
We feel that there are justified reasons for concern.
While Prof Zhou and his colleagues have a great deal of experience with embryonic stem cells and have published very impressive research on that topic, the preclinical data for this trial is limited. In 2015, the research group published this report:
Title: Lmx1a enhances the effect of iNSCs in a PD model
Authors: Wu J, Sheng C, Liu Z, Jia W, Wang B, Li M, Fu L, Ren Z, An J, Sang L, Song G, Wu Y, Xu Y, Wang S, Chen Z, Zhou Q, Zhang YA.
Journal: Stem Cell Res. 2015 Jan;14(1):1-9.
PMID: 25460246 (This article is OPEN ACCESS if you would like to read it)
In this study, the researchers engineered embryonic stem cells to over-produce a protein called LMX1A to help produce dopamine neurons. LMX1A is required for the development of dopamine neurons (Click here to read more about this). The investigators then grew these cells in cell culture and compared their ability to develop into dopamine neurons against embryonic stem cells with normal levels of LMX1A. After 14 days in cell culture, 16% of the LMX1A cells were dopamine neurons, compared to only 5% of the control cells.
When the investigators transplanted these cells into a mouse model of Parkinson’s disease, they found that the behavioural recovery in the mice did not differ from the control injected mice, and when they looked at the brains of the mice 11 weeks after transplantation “very few engrafted cells had survived”.
In addition to this previously published work, the Chinese team do have unpublished research on 15 monkeys that have undergone the neuronal-precursor cell transplantation procedure having had Parkinson’s disease induced using a neurotoxin. The researchers have admitted that they initially did not see any improvements in movement (which is expected given the slow maturation of the cells). At the end of the first year, however, they examined the brains of some of the monkeys and they found that the transplanted stem cells had turned into dopamine-releasing cells (exactly what percentage of the cells were dopamine neurons is yet to be announced). The monkey study has been running for several years now and they have seen a 50% improvement in the motor ability of the remaining monkeys, supported by brain imaging data. The publication of this research is in preparation, but it probably won’t be available until after the trial has started.
So yes, there is a limited amount of preclinical research supporting the clinical trial.
As for concerns regarding the type of cells that are going to be transplanted:
Embryonic stem cells have robust tumour forming potential. If you inject them into the brain of mice, there is the potential for them to develop into dopamine neurons, but also tumours:
Title: Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model
Authors: Bjorklund LM, Sánchez-Pernaute R, Chung S, Andersson T, Chen IY, McNaught KS, Brownell AL, Jenkins BG, Wahlestedt C, Kim KS, Isacson O.
Journal: Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2344-9.
PMID: 11782534 (This article is OPEN ACCESS if you want to read it)
In this study, the researchers found that of the twenty-five rats that received embryonic stem cell injections into their brains to correct the modelled Parkinson’s disease, five rats died before completed behavioural assessment and the investigators found teratoma-like tumours in their brains – less than 16 weeks after the cells had been transplanted.
A teratoma (white spot) inside a human brain. Source: Radiopaedia
Given this risk of tumour formation, research groups in the cell transplantation field have been trying to push the embryonic stem cells as far away from their original pluripotent state and as close to a dopamine fate as possible without producing mature dopamine neurons which will not survive the transplantation procedure very well.
Prof Zhou’s less mature neuronal-precursor cells are closer to embryonic stem cells than dopamine neurons on this spectrum than the kinds of cells other research groups are testing in cell transplantation experiments. As a result, we are curious to know what precautions the investigators are taking to limit the possibility of an undifferentiated, still pluripotent embryonic stem cell from slipping into this study (the consequences could be disastrous). And given their results from the LMX1A study described above, we are wondering how they are planning to push the cells towards a dopamine fate. If they do not have answers to this issues, they should not be rushing to the clinic with these cells.
So yes, there are reasons for concern regarding the cells that the researchers plan to use in this clinical trial.
And, as with the International Stem Cell Corporation stem cell trial in Australia, we also worry that the follow up-period (or endpoint in the study) of 12 months is not long enough to determine the efficacy of these cells in improving Parkinson’s rating scores and brain imaging results. All of the previous clinical research in this field indicates that the transplanted cells require years of maturation before their dopamine production has an observable impact on the participant. Using 12 months as an end point for this study is tempting a negative result when the long term outcome could be positive.
As we mentioned above, any negative outcomes for these studies could have dire consequences for the field as a whole.
So what does it all mean?
Embryonic stem cells hold huge potential in the field of regenerative medicine. Their ability to become any cell type in the body means that if we can learn how to control them correctly, these cells could represent a fantastic new tool for future cell replacement therapies in conditions like Parkinson’s disease.
Strong demand for such therapies from groups like the Parkinsonian community, has resulted in research groups rushing to the clinic with different approaches using these cells. Concerns as to whether such approaches are ready for the clinic are warranted, if only because mistakes by individual research groups/consortiums in the past have caused delays for everyone in the field.
While China is very keen (and should be encouraged) to take bold steps in its ambition to be a world leader in this field, open and transparent access to extensive preclinical research would help assuage concerns within the research community that prudent care is being taken heading forward.
We’ll keep you aware of developments in this clinical trial.
EDITORIAL NOTE No.1 – It is important for all readers of this post to appreciate that cell transplantation for Parkinson’s disease is still experimental. Anyone declaring otherwise (or selling a procedure based on this approach) should not be trusted. While we appreciate the desperate desire of the Parkinson’s community to treat the disease ‘by any means possible’, bad or poor outcomes at the clinical trial stage for this technology could have serious consequences for the individuals receiving the procedure and negative ramifications for all future research in the stem cell transplantation area.
EDITORIAL NOTE No.2 – the author of this blog is associated with research groups conducting the current Transeuro transplantation trials and the proposed G-Force embryonic stem cell trials planned for 2018. He has endeavoured to present an unbiased coverage of the news surrounding the current clinical trials, though he shares the concerns of the Parkinson’s scientific community that the research supporting the current Australian trial is lacking in its thoroughness and will potentially jeopardise future work in this area. He is also concerned by the lack of peer-reviewed published research on cell transplantation in models of Parkinson’s disease for the proposed clinical studies in China.
The banner for today’s post was sourced from Ozy
Parkinson’s disease is a neurodegenerative condition. That means that cells in the brain (neurons) are dying. By the time the motor features of Parkinson’s disease (rigidity, slowness of movement, and a resting tremor or shaking of a limb) become apparent to an individual, they will have lost 60-70% of the dopamine neurons in a region of the brain called the midbrain.
Above are slices of human brain, taken from the midbrain of a healthy control subject (left) and an individual who died with Parkinson’s disease. The dopamine cells in the control subject can be seen on both sides of the brain with the eye because they produce a chemical (neuromelanin) that makes them black. These cells are noticeably absent in the Parkinsonian brain. Source: Springer
While there is a lot of research investigating how to stop or slow down the disease, at present, the only realistic way to deal with what has already been lost is to replace it. This could be done with cell transplantation.
Cell transplantation has had a long and colourful history of trial and error with regards to Parkinson’s disease. Importantly, given that there is currently no clinically approved cell transplantation procedure for Parkinson’s disease, the approach must be considered experimental, at best. This has not, however, stop numerous unscrupulous practitioners from advertising their services and preying on desperate individuals. They offer expensive operations, that have little if any peer-reviewed scientific evidence backing them.
Let us repeat: there is currently NO clinically approved cell transplantation procedure for Parkinson’s disease.
The history of cell transplantation in Parkinson’s disease
There has been an enormous amount of cell transplant work conducted in rodent models of Parkinson’s disease – in which the dopamine system is lesioned unilaterally. Many different types of cells have been used, but by far the most successful have been immature dopamine neurons (collected from embryos). The success of that work resulted in numerous clinical trials in the 1990s. Those trials began with a group in Lund (Sweden) who, in 1991, transplanted fetal midbrain tissue into six patients: four with advanced idiopathic Parkinson’s disease and two from the ‘Frozen addicts’ cohort (see the book “The case of the frozen addicts” for an explanation of these two individuals). Similar programmes had been initiated in England, Spain, Mexico, Cuba, France, and Belgium. These were all considered to be relatively successful, except for the fact that they were all open-label/not blinded studies, meaning that everyone involved in the study knew who was getting transplanted.
In the USA, these developments took place amid a major debates about the ban on federal funding for fetal tissue research that had been introduced by the Reagan administration in 1988. The Clinton administration lifted this ban in January, 1993, and this reversal opened the way for the National Institutes of Health (NIH) to provide funding for the two placebo-controlled studies. Those two trials were:
Trial no. 1: The Colorado/Columbia Trial:
A double blind trial in which 40 subjects (with advanced PD) received transplants of fetal midbrain tissue and 34 additional subjects (with advanced PD) had a sham surgery and were considered controls. Critically, neither the subjects nor the practitioners knew who was in which group. No patients in either arm of the study received immunosuppression, meaning that their immune systems were free to attack the injected cells (which would have been considered foreign by the body). The patients were followed up for 1 year after surgery and the success of the trial was judged on the basis of a self-report rating of clinical improvement or deterioration, scored by patients in their own homes and then sent to the investigator. The report of the study was published in the New England Journal of Medicine:
Title: Transplantation of embryonic dopamine neurons for severe Parkinson’s disease.
Authors: Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, Dillon S, Winfield H, Culver S, Trojanowski JQ, Eidelberg D, Fahn S.
Journal: New England Journal of Medicine 2001 Mar 8;344(10):710-9.
Trial no. 2: The Tampa Bay Trial:
34 patients were randomly assigned either to receive a transplant of fetal midbrain tissue or to undergo a sham surgery. All patients received 6 months of immunosuppression after surgery. The primary endpoint for this study was a significant difference between the groups at 24 months after surgery. The report of this study was published in the journal, Annals of Neurology:
Title: A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease.
Authors: Olanow CW, Goetz CG, Kordower JH, Stoessl AJ, Sossi V, Brin MF, Shannon KM, Nauert GM, Perl DP, Godbold J, Freeman TB.
Journal: Ann Neurol. 2003 Sep;54(3):403-14.
Both of these clinical studies failed to show any significant improvement at their endpoints. In addition, 15% – 50% of transplanted subjects developed what are called ‘graft induced dyskinesias’ (or GID’s). This is where the subjects display uncontrollable/erratic movement. Interestingly, patients under 60 years of age did show signs of improvement on when assessed both clinically (using the UPDRS-III) and when assessed using brain imaging techniques (increased F-dopa uptake on PET). But the overall negative results left a shadow over the technique for the better part of a decade.
So what is currently happening?
There are new clinical trials currently underway for cell transplantation in Parkinson’s disease. Primary amongst these is the Transeuro being conducted in Europe.
The Transeuro trial. Source: Transeuro
The Transeuro trial is an open label study, involving 40 subjects, transplanted in sites across Europe. They will receive immunosuppression for at least 12 months post surgery, and the end point of the study will be 3 years post surgery, and based on brain imaging of dopamine release from the transplanted cells (PET scans). Based on the previous double blind studies discussed above, only subject under 65 years of age have been enrolled in the study.
The European consortium behind the Transeuro trial. Source: Transeuro
Do the transplants slow down the disease?
The evidence thus far is not clear, but some of the original patients from the 1991 Sweden trial were able to stop/cut back on their L-dopa treatment. Recently, some of the patients who received transplants have pass away and their brains have been examined post-mortem. One very interesting finding is that some of the cells in the transplants (1-5%) have lewy bodies in them. This suggests that the disease is passed on to the healthy transplanted cells in some way.
Above are photos of neurons from the post-mortem brains of people with Parkinson’s that received transplants. White arrows in the images above indicate lewy bodies inside transplanted cells. Source: The Lancet
For more information on this, see these articles:
Title: Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation.
Authors: Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, Lashley T, Quinn NP, Rehncrona S, Björklund A, Widner H, Revesz T, Lindvall O, Brundin P.
Journal: Nature Medicine. 2008 May;14(5):501-3.
Title: Lewy body pathology in long-term fetal nigral transplants: is Parkinson’s disease transmitted from one neural system to another?
Authors: Kordower JH, Brundin P.
Journal: Neuropsychopharmacology. 2009;3 (1):254.
PMID: 19079079 (this review article is freely available)
Thus it would appear that cell transplantation will not stop the disease. At best it will simply allow us to replace the lost cells and reverse some of the motor related features of the condition. Ideally, this approach would be conducted in concert with additional therapies that slow or halt the disease (such as a vaccine possibly).
What next for cell transplantation?
Given the moral and ethical issues surrounding the use of fetal tissue, research has shifted towards using embryonic stem (ES) cells and turning them into midbrain dopamine neurons. And the results here have been very promising, with recent reports suggesting that ES cells can be converted into dopamine neurons and transplanted into rodent models of Parkinson’s disease with equal efficiency to that of fetal midbrain tissue.
Title: Human ESC-derived dopamine neurons show similar preclinical efficacy and potency to fetal neurons when grafted in a rat model of Parkinson’s disease.
Authors: Grealish S, Diguet E, Kirkeby A, Mattsson B, Heuer A, Bramoulle Y, Van Camp N, Perrier AL, Hantraye P, Björklund A, Parmar M.
Journal: Cell Stem Cell. 2014 Nov 6;15(5):653-65.
The take home message regarding cell transplantation is that at present it represents one of the only ways to replace what has been lost, but as of yet there is not an approved protocol for this approach in humans. As we said above, at best this should be considered experimental, and individuals selling expensive procedures should be avoided. The future looks very bright for this field, however, and we will keep you updated as more information comes to hand.
EDITORIAL NOTE: Happy new year everyone! We look forward to bringing you all the exciting news related to the science of Parkinson’s disease in 2016.