Cell replacement therapy is a key component of any “cure” for Parkinson’s – replacing the cells that have been lost over the course of the condition.
Cell transplantation of dopamine neurons has a long track record of both preclinical and clinical development and represents the most developed of the cell replacement approaches.
Two weeks ago, the biotech firm BlueRock Therapeutics announced an agreement under which the pharmaceutical company Bayer AG would fully acquire the company.
In today’s post we will discuss why this is major news for the Parkinson’s community and an important development for the field of cell replacement therapy.
On the 8th August, Bayer AG and BlueRock Therapeutics announced an agreement under which Bayer will “fully acquire BlueRock Therapeutics, a privately held US-headquartered biotechnology company focused on developing engineered cell therapies in the fields of neurology, cardiology and immunology, using a proprietary induced pluripotent stem cell (iPSC) platform” (Source).
What is BlueRock Therapeutics?
Versant Ventures is a leading venture capital firm that specializes in investing “in game changing biopharmaceuticals, medical devices, and other life science opportunities”. Leaps by Bayer is an effort by the Pharmaceutical company Bayer at “spearheading a movement to make paradigm-shifting advances in the life sciences – targeting the breakthroughs that could fundamentally change the world for the better”.
The news on the 8th August means Bayer will acquire the remaining stake for approximately US$240 million in cash (to be paid upfront) and an additional US$360 million which will be payable upon the achievement of certain pre-defined development milestones.
Given that Bayer currently holds 40.8% stake in BlueRock Therapeutics, this announcement values the company at approximately US$1 billion.
Interesting, but what exactly does BlueRock do?
On the 12th and 13th November, Parkinson’s UK held their biennial research conference in York.
It is not only an opportunity for the charity to showcase some of the research that they have funded over the last few years, but it was also a chance for members of the Parkinson’s research community to come together to share ideas, network and form new collaborations.
I was lucky enough to attend the event this year, and wanted to share some of the take away messages from the conference with the readers.
In today’s post, we will review Parkinson’s UK 2018 research conference (#Parkinsons2018).
Parkinson’s UK is the largest Parkinson’s research and support charity in the United Kingdom. Since 2015, they have invested over £18 million in a variety of research projects focused on all aspects of Parkinson’s – from new experimental treatments to the Parkinson’s UK Brain Bank.
Every two years, Parkinson’s UK holds a conference highlighting some of the research that the organisation has funded over the last few years. The meeting is usually held in the beautiful walled city of York – lots of history and narrow streets to explore.
Th “The Shambles” in York. Source: hauntedrooms
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 Pharmaceuticals and Medical Devices Agency (PMDA) – the Japanese regulatory agency that oversees clinical trials – 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.
Two months ago a research report was published in the scientific journal ‘Nature’ and it caused a bit of a fuss in the embryonic stem cell world.
Embryonic stem (ES) cells are currently being pushed towards the clinic as a possible source of cells for regenerative medicine. But this new report suggested that quite a few of the embryonic stem cells being tested may be carrying genetic variations that could be bad. Bad as in cancer bad.
In this post, I will review the study and discuss what it means for cell transplantation therapy for Parkinson’s disease.
For folks in the stem cell field, the absolute go-to source for all things stem cell related is Prof Paul Knoepfler‘s blog “The Niche“. From the latest scientific research to exciting new stem cell biotech ventures (and even all of the regulatory changes being proposed in congress), Paul’s blog is a daily must read for anyone serious about stem cell research. He has his finger on the pulse and takes the whole field very, very seriously.
For a long time now, Paul has been on a personal crusade. Like many others in the field (including yours truly), he has been expressing concern about the unsavoury practices of the growing direct-to-consumer, stem cell clinic industry. You may have seen him mentioned in the media regarding this topic (such as this article).
The real concern is that while much of the field is still experimental, many stem cell clinics are making grossly unsubstantiated claims to draw in customers. From exaggerated levels of successful outcomes (100% satisfaction rate?) all the way through to talking about clinical trials that simply do not exist. The industry is badly (read: barely) regulated which is ultimately putting patients at risk (one example: three patients were left blind after undergoing an unproven stem cell treatment – click here to read more on this).
While the stem cell research field fully understands and appreciates the desperate desire of the communities affected by various degenerative conditions, there has to be regulations and strict control standards that all practitioners must abide by. And first amongst any proposed standards should be that the therapy has been proven to be effective for a particular condition in independently audited double blind, placebo controlled trials. Until such proof is provided, the sellers of such products are simply preying on the desperation of the people seeking these types of procedures.
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
With the end of the 2016, we thought it would be useful and interesting to provide an overview of where we believe things are going with Parkinson’s disease research in the new year. This post can be a primer for anyone curious about the various research activities, and food for thought for people who may have some fresh ideas and want to get involved with the dialogue.
Never before has so much been happening, and never before has there been greater potential for real change to occur. It is a very exciting time to be involved in this field, and it really does feel like we are on the cusp of some major discoveries.
In today’s post we will outline what to expect from Parkinson’s research in 2017.
Things to look forward to. Source: Dreamstime
Before we start: something important to understand –
The goal of most of the research being conducted on Parkinson’s disease is ultimately focused on finding a cure.
But the word ‘cure’, in essence, has two meanings:
- The end of a medical condition, and
- The substance or procedure that ends the medical condition
These are two very different things.
And in a condition like Parkinson’s disease, where the affected population of people are all at different stages of the disease – spanning from those who are not yet aware of their condition (pre-diagnosis) to those at more advanced stages of the disease – any discussion of a ‘cure for Parkinson’s disease’ must be temporal in its scope.
In addition to this temporal consideration, everyone is different.
A ‘cure’ for one person may not have an impact on another person – particularly when genetics is included in the equation. Currently there is a clinical trial which is only being tested on people with Parkinson’s disease who have a particular genetic mutation (Click here to read more about this).
With all of that said, there are 4 key areas of ongoing/future research:
- Defining and understanding the biology of the condition
- Early detection
- Slowing/halting the disease
- Replacing what has been lost
EDITOR’S NOTE HERE: While we appreciate that this list does not take into account important research dealing with the improving the day-to-day living and quality of life of those affected by Parkinson’s disease (such as prevention of falling, etc), we are primarily focusing here on finding a ‘cure’.
Let’s now have a look at and discuss each of these key areas of research:
Defining and understanding the biology
Complicated stuff. Source: Youtube
The first key area of research feeds into all of the others.
It is only through a more thorough understanding of the mechanisms underlying Parkinson’s disease that we will be able to provide early detection, disease halting therapies, and cell replacement options. A better conception of the disease process would open doors in all of the other areas of research.
Given the slow pace of progress thus far, you will understand that this area of research is not easy. And it is made difficult by many issues. For example, it may be that we are blindly dealing with multiple diseases that have different causes and underlying mechanisms, but display the same kinds of symptoms (rigidity, slowness of movement and a resting tremor). Multiple diseases collectively called ‘Parkinson’s’. By not being able to differentiate between the different diseases, we have enormous confounding variables to deal with in the interpretation of any research results. And this idea is not as far fetched as it may sound. One of the most common observations within a group of people with Parkinson’s disease is the variety of disease features the group presents. Some people are more tremor dominate, while others have severe rigidity. Who is to say that these are not manifestations of different diseases that share a common title (if only for ease of management).
This complication raises the possibility that rather than being a disease, ‘Parkinson’s’ may actually be a syndrome (or a group of symptoms which consistently occur together).
Recently there have been efforts to deal with this issue within the Parkinson’s research community. We have previously written about the improved diagnostic criteria for Parkinson’s disease (click here to read that post). In addition, as we mentioned above, some new clinical trials are focusing on people with very specific types of Parkinson’s disease in which the subjects have a particular genetic mutation (Click here to read more about this). Better stratification of the disease/s will help us to better understand it. And with the signing into law of the 21 century Cures Act by President Obama, the Parkinson’s research community will have powerful new data collection tools to use for this purpose – in addition to more funding for research at the National Institute of Health (Click here to red more on this).
More knowledge of the basic biology of Parkinson’s disease is critical to the road forward. Whether the Parkinson’s disease-associated proteins, like alpha synuclein, are actually involved with the cell death associated with the condition is a question that needs to be resolved. If they are simply the bio-product of an alternative (unseen) disease process is important to know.
It is impossible to know what the new year will bring for new discoveries in the basic biology of Parkinson’s disease. Compared to 20 years ago, however, when the new discoveries were few and far between, 2017 will bring with it major new discoveries every month and we’ll do our best to report them here.
Early detection for Parkinson’s disease
Consider the impact of a pregnancy test on a person’s life. Source: Wikipedia
Ethically, the ‘early detection’ area of research can be a bit of a mine field, and for good reasons. You see, if we suddenly had a test that could accurately determine who is going to get Parkinson’s disease, we would need to very carefully consider the consequences of using it before people rush to start using it in the clinic.
Firstly there are currently no disease halting treatments, so early knowledge of future potential events may not be useful information. Second, there is the psychological aspect – such information (in light of having no treatment) may have a dramatic impact on a person’s mental wellbeing. And thirdly, such information would have huge implications for one’s general life (for example, individuals are legally bound to tell their banks and insurance companies about such information). So you see, it is a very tricky field to tackle.
Having said all of that, there are some very positive aspects to early detection of Parkinson’s disease. Early indicators (or biomarkers) may tell us something new about the disease, opening novel avenues for research and therapeutic treatments. In addition, early detection would allow for better tracking of the disease course, which would enhance our ideas about how the condition starts and changes over time.
There are numerous tests being developed – from blood tests (click here and here for posts we wrote about this topic) to saliva tests (again, click here for our post on this topic). There are even a simple urine test (click here for our post on this) and breath analysis test (click here for more on this) being developed. And there are ever increasing brain imaging procedures which may result in early detection methods (Click here for more on this).
How does the Parkinson’s research community study early detection of Parkinson’s disease though? Well, we already know that people with rapid eye movement (REM) sleep disorder problems are more likely to develop Parkinson’s disease. Up to 45 percent of people suffering REM sleep behaviour disorders will go on to develop Parkinson’s disease. So an easy starting point for early detection research is to follow these people over time. In addition, there are genetic mutations which can pre-dispose individuals to early onset Parkinson’s disease, and again these individuals can be followed to determine common ‘biomarkers’ (aspects of life that are shared between affected individuals). Epidemiological studies (like the Honolulu Heart study – click here for more on this) have opened our eyes to keep features and aspects of Parkinson’s disease that could help with early detection as well.
Slowing/halting Parkinson’s disease
One of the most significant findings in Parkinson’s disease research over the last few years has been the discovery that transplanted dopamine cells can develop Lewy bodies over time. It is very important for everyone to understand this concept: healthy embryonic cells were placed into the Parkinsonian brain and over the space of one or two decades some of those cells began to display the key pathological feature of Parkinson’s disease: dense, circular clusters of protein called Lewy bodies.
The implications of this finding are profound: Healthy cells (from another organism) developed the features of Parkinson’s disease. And this is (presumably) regardless of the genetic mutations of the host. It suggests that the disease spreads by being passed from cell to cell. There is a very good open-access article about this in the journal Nature (click here to read that article).
Slowing down the progression of Parkinson’s disease is where most of the new clinical trials are focused. There are numerous trials are focused on removing free-floating alpha synuclein (the main protein associated with Parkinson’s disease). This is being done with both vaccines and small molecules (such as antibodies). Beyond possibly slowing the disease, whether these clinical trials are successful or not, they will most definitely provide an important piece of the puzzle that is missing: is alpha synuclein involved with the spread of the disease? If the trials are successful, this would indicate ‘Yes’ and by blocking alpha synuclein we can slow/halt the spread of the disease. If the trials fail, this would suggest that alpha synuclein is not responsible, and indicate that we need to focus our research attention elsewhere.
2017 will be very big year for Parkinson’s disease as some of these clinical trials will be providing our first glimpse at resolving this major question.
Replacing what is lost
Cell transplantation for Parkinson’s disease. Source: AtlasofScience
So if we discover a means of stopping the disease with a vaccine or a drug, this will be fantastic for people who would be destined to develop the condition… but what about those still living with the disease. Halting the condition will simply leave them where ever they are on the course of the disease – a rather unappealing situation if one is in the latter stages of the condition.
Cell transplantation is one means of replacing some of the cells that have been lost in this disease. Most of the research is focused on the dopamine neurons whose loss is associated with the appearance of the movement features of Parkinson’s disease.
Unfortunately, this area of research is more ‘blue sky’ in terms of its clinical application. It will be some time before cell transplantation has a major impact on Parkinson’s disease. And while many research groups have plans to take this approach to the clinic, there are currently just two ongoing clinical trials for cell transplantation in Parkinson’s disease:
The former is behind schedule due to the technical matters (primarily the source of the tissue being transplanted) and the latter is controversial to say the least (click here and here to read more). In the new year we will be watching to see what happens with a major research consortium called G-Force (strange name we agree). They are planning to take dopamine neurons derived from embryonic stem cells to clinical trials in 2018. Embryonic stem cells represents a major source of cells for transplantation as they can be expanded in a petri dish (millions of cells from just one cell). If they can be pushed in the right direction and they develop into dopamine neurons, they would allow people to start having some of the cells that they have lost to Parkinson’s disease to be replaced.
Above we have discussed the key areas of Parkinson’s disease (dealing with ‘finding a cure’) for 2017. We would love to hear your thoughts on them. If not, here on the SoPD, then somewhere else. Please get involved with the discussion in which ever forum you choose. Speak up and add your personal account of things to the discussion.
It is only through the sharing of ideas, information, and experiences that we are going to figure out this debilitating condition.
And now we are going to change focus and discuss what we are expecting/hoping for in the new year (particularly from the clinical side of things):
Bright future ahead
Looking ahead to better times. Source: Journey with Parkinson’s (Great blog!)
So looking ahead, what is happening:
Recently some major players have come together to focus on Parkinson’s disease:
- Bayer and healthcare investment firm Versant Ventures joined forces to invest $225 million in stem-cell therapy company BlueRock Therapeutics. This venture will be focused on induced pluripotent stem cell (iPSC)-derived therapeutics for cardiovascular disease and neurodegenerative disorders, particularly Parkinson’s disease (co-founders Lorenz Studer and Viviane Tabar are world renowned experts in the field of cell transplantation for Parkinson’s disease). Importantly, BlueRock has acquired rights to a key iPSC intellectual property from iPS Academia Japan, and with 4 years of funding they will be looking to make things happen (Click here to read more on this).
- Evotec and Celgene are also jumping into the IPS cell field, but they are collaborating to screen for novel drug targets. (Click here to read more on this).
- For a long time we have been hearing that the major tech company Apple is working on software and devices for Parkinson’s disease. They already provide ResearchKit and CareKit software/apps. Hopefully in the new year we will hear something about their current projects under development (Click here to read more on this).
- In February of 2016, seven of the world’s largest pharmaceutical companies signed up to Critical Path for Parkinson’s set up by Parkinson’s UK. It will be interesting in the new year to see what begins to develop from this initiative.
- Parkinson’s UK has also set up the Virtual Biotech, which is looking at providing faster means for new drugs to be brought to market. Hopefully this will take off in 2017.
In addition, there are many clinical trials starting and also announcing results. Here are the top 20 that we are keeping an eye on:
- Herantis Pharma, a Finnish pharmaceutical company, will begin recruiting 18 people with Parkinson’s disease for their Conserved Dopamine Neurotrophic Factor (or CDNF) clinical trial. CDNF is very similar to GDNF which we have previously discussed on this site (Click here for that post). Herantis will be collaborating with another company, Renishaw, to deliver the CDNF into the brain (Click here to read more on this trial).
- The results of the double-blind, placebo controlled clinical study of the diabetes drug Exenatide will be announced in 2017. We have previously discussed this therapy (click here and here for more on this), and we eagerly await the results of this study.
- AAV2-hAADC, which is a gene therapy treatment – a virus that works by allowing cells in the body other than neurons to process levodopa. The results of the phase one trial were successful (click here to read about those results) and the company (Voyager Therapeutics) behind the product are now preparing for phase 2 trials (Click here for more on this).
- Donepezil (Aricept®) is an Alzheimer’s therapy that is being tested on dementia and mild cognitive impairment in Parkinson’s disease (Click here for more on this trial).
- Oxford Biomedica is attempting to proceed with their product, OXB-102, which is a gene therapy treatment – a virus that modifies neurons so that they produce dopamine. Phase 1 successful, but did not show great efficacy. Phase 2 is underway but not recruiting (click here for more on this trial).
- Biotie is proceeding with their product, SYN120, which is new class of combination drug (dual antagonist of the serotonergic 5-HT6 and 5-HT2A receptors) which is being tested as a treatment of cognition and psychosis in Parkinson’s disease (Click here for more on this).
- Acorda Therapeutics is continuing to take the new inhalable form of L-dopa, called CVT-301 to the clinic. Phase 1 trials were successful (Click here and here to read more) and phase 2 trials are being planned.
- Related to caffeine, Istradefylline, is an A2A receptor antagonist, already approved in Japan, that is designed to reduce “off” time and suppress dyskinesias. Phase 1 testing was successful (Click here for more on this) and phase 2 trials are being planned.
- Another product from Biotie, Tozadenant, is an A2A receptor antagonist designed to reduce “off” time and suppress dyskinesias.
- UniQure was developing AAV2-GDNF – A gene therapy treatment – a virus designed to deliver GDNF (a naturally occurring protein that may protect dopamine neurons) in the brain (Click here for more on this trial). The company has recently announced cost cutting, however, and removed AAV2-GDNF from it’s list of products under development, so we are unsure about the status of this product.
- AstraZeneca are taking their myeloperoxidase (MPO) inhibitor, AZD3241, through phase 2 trials at the moment (Click here for more on this trial). Oxidative stress/damage and the formation of excessive levels of reactive oxygen species plays a key role in the neurodegeneration associated with Parkinson’s disease. MPO is a key enzyme involved in the production of reactive oxygen species. By blocking it, AstraZeneca hopes to slow/halt the progression of Parkinson’s disease.
- Genervon Biopharmaceuticals will be hopefully be announcing more results from their phase 2 clinical trial of GM 608 (Click here for more on the trial). GM 608 has been shown to protect neurons against inflammatory factors floating around in the brain. Initial results looked very interesting, though the study was very small (Click here for more on those results).
- Neurimmune (in partnership with Biogen) is proceeding with their product, BIIB054, which is an immunotherapy – an antibody that clears free floating alpha-synuclein in an attempt to halt the spread of the disease (Click here for more on this trial).
- Neuropore is continuing to move forward with their product, NPT200-11, which is a drug designed to stabilize alpha-synuclein, preventing it from misfolding and aggregating. Phase 1 trial was successful (Click here and here to read more on this). Phase 2 trials are being planned.
- Prothena are very pleased with their product, PRX002 (an immunotherapy – an antibody that clears free floating alpha-synuclein in an attempt to halt the spread of the disease (similar to BIIB054 described above)). Phase 1 trials were successful (Click here for more on this).
- Edison Pharma is currently conducting a phase 2 trial of Vatiquinone on Visual and Neurological Function in Patients with Parkinson’s Disease (Click here for more on this trial). Vatiquinone modulates oxidative stress by acting on the mitochondria on cells.
- Isradipine (Prescal®) – a calcium channel blocker that is approved for treatment of high blood pressure – is being tested in Parkinson’s disease by the Michael J Fox Foundation (Click here for more on this).
- Inosine – which is a nutritional supplement that converts to urate, a natural antioxidant found in the body – is going to be tested in a phase 3 clinical trial (Click here for more on that trial).
- In 2015, Vernalis has licensed its adenosine receptor antagonist programme (including lead compound V81444) to an unnamed biotech company. We are hoping to see the results of the phase 1 trial that was conducted on V81444 for Parkinson’s disease sometime in the new year (Click here to read more about that trial).
- And finally, we are hoping to see progress with Nilotinib (Tasigna®) – A cancer drug that has demonstrated great success in a small phase 1 trial of Parkinson’s disease. Unfortunately there have been delays to the phase 2 trial due to disagreements as to how it should be run (Click here to read more). We have been following this story (Click here and here and here to read more), and are very disappointed with the slow progress of what could potentially be a ‘game-changer’ for the Parkinson’s community. Hopefully the new year will bring some progress.
Please note that this is not an exhaustive list – we have missed many other compounds being tested for Parkinson’s disease. For example there are always alternative versions of products currently on the market being tested in the clinic (eg. new L-dopa products). We have simply listed some of the novel approaches here that we are particularly interested in.
See the Michael J Fox Foundation Pipeline page for more information regarding clinical trials for Parkinson’s disease.
EDITORIAL NOTE HERE: All of the team at the SoPD wants to wish everyone a very enjoyable festive season where ever you are. And all the very best for the new year!
Happy New Year everyone,
The team at SoPD
The banner for today’s post was sourced from Weknowyourdreams
Science conference. Source: JPL
This week over 40,000 neuroscientists from all over the world have gathered for the annual Society for Neuroscience conference in sunny San Diego. It is 5 days of non-stop presentations of scientific results.
One of the presentations made this year was delivered by Dr Russell Kern, executive vice president and chief scientific officer of International Stem Cell Corp (ISCO). It dealt with the controversial on-going stem cell clinical trial in Australia. In the presentation, Dr Kern outlined the study and gave an update on the first patient in the Phase 1 clinical trial, who was transplanted at the end of July. The second patient is scheduled be treated in the next three weeks. A total of 12 are expected to be treated.
During the three months following the first surgery, the attending physicians observed no signs of complications (which is a very good thing). Unfortunately, according to San Diego Union Tribute, Dr Kern is then said to have implied that ‘there are some indications of efficacy in relieving symptoms of the movement disorder’. In addition, Dr Kern suggested that ‘the patient’s handwriting has improved’.
Long time readers of this blog know that we have been extremely critical of this trial from the start (Click here and here to read them). We make no apologise for this. The pre-clinical data that has been presented thus far in no way justifies taking these particular cells to the clinic. We believe it irresponsible. And our opposition is supported by many other researchers in the Parkinson’s research field (Click here for an example).
It defies belief, however, that Dr Kern would suggest to a conference audience or a media outlet that a patient who is 3 months post surgery could be exhibiting functional improvements. It is widely acknowledged in the Parkinson’s disease research field that it takes 2-3 years for the cells (that are transplanted into the brain) to mature and become functional (click here for more on this). In addition, during their preclinical studies Dr Kern and his colleagues observed very little in the way of behavioural improvements 12 months after transplantation (when compared to control conditions), so how is it that they are seeing such rapid improvements in their first human subject?
If Dr Kern’s suggestions of functional improvements are based solely on the unblinded observations of the clinician and the patient, then sharing such information publicly is extremely inappropriate. Unprofessional at best, but potentially unethical. At the very least, any suggestions of functional recovery in cases like these should be supported by brain scans (indicating increases in dopamine activity) and blinded, unbiased investigator scoring. Otherwise any reported outcomes could simply be due to the placebo effect (as the patient knows that he has been transplanted), and thus not valid for a Parkinson’s community desperate to see positive results in a potential therapy.
We also have concerns regarding the financial feasibility of the current study. Shares in ISCO have fallen from their giddy highs of $2.50 a share back in 2010 to a recent all-time low of just $0.055 (valuing the company at less than $6 million). According to their most recent financial statement, the company is burning $343,000 per month (for the year ended December 31, 2015), and the company ended 2015 with a cash position of just over $530,000. They partly resolved this problem in March of this year by issuing more shares (Source), but one does worry that this kind of activity can not be maintained indefinitely.
Here at the SoPD, we are very keen for cell transplantation to become a viable treatment option for people with Parkinson’s disease in the very near future. But the approach must be rigorously tried and tested, and presented to the highest standards before it can be considered feasible. As we have said before, the standards surrounding this particular trial (demonstrated by inappropriate disclosures of information during an ongoing clinical trial) are lacking.
FULL DISCLOSURE – 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 this current clinical trial, but when unacceptable statements are being made to media outlets, well, he is human and it is difficult to remain unbiased. 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.
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.