Tagged: International stem cell corporation

The EMPRSN talk #1

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.

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New stem cell transplantation trial for Parkinson’s proposed in China

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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.


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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.

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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.

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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):

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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).

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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:

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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):

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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???

Two reasons:

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).

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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.

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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.

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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.

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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.

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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.

In testing the safety and efficacy of these cells, the trial will have two primary outcome measures:
  1. Incidence of treatment-emergent adverse events, as assessed by brain imaging and blood examination at 6 months post transplant.
  2. 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:

  1. 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.
  2. 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.
  3. 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.

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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:

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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:

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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.

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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

Update – ISCC Stem cell Transplantation trial

 

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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.

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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. 

Update: Stem cells trial for Parkinson’s disease

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Last night surgeons at the Royal Melbourne Hospital, conducted an 8 hour surgery during which stem cells were injected into 14 sites in the brain of a 64 year old person with Parkinson’s disease. This was the first of 12 surgeries being conducted in a phase 1 clinical trial that will assess the safety of this particular type of stem cell in human.

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Surgeons at work. Source: Reuters

Some media outlets have reported the surgery as taking us ‘one step closer to a cure for Parkinson’s disease’ (Click here, here, and here to see their reports). We here at the SoP.com are less excited by this new development, having previously expressed serious concerns about this trial (Click here for that post). We believe that the preclinical data presented thus far does not support going forward to the clinic prematurely with this particular type of stem cell.

Our primary concerns arise from some of the most recent preclinical work published by the company – International Stem Cell Corporation (ISCO) – behind the trial, particularly their preclinical non-human primate work:

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Title: Neural Stem Cells Derived from Human Parthenogenetic Stem Cells Engraft and Promote Recovery in a Nonhuman Primate Model of Parkinson’s Disease.
Authors: Gonzalez R, Garitaonandia I, Poustovoitov M, Abramihina T, McEntire C, Culp B, Attwood J, Noskov A, Christiansen-Weber T, Khater M, Mora-Castilla S, To C, Crain A, Sherman G, Semechkin A, Laurent LC, Elsworth JD, Sladek J, Snyder EY, Jr DE, Kern RA.
Journal: Cell Transplant. 2016, 25 (11), 1945-1966.
PMID: 27213850     (This article is OPEN ACCESS if you would like to read it)

In this study, 12 African Green monkeys with induced Parkinson’s disease (caused by the neurotoxin MPTP) were injected in the brain with the ISCO’s stem cells (called hpNSCs). The cells are injected into two areas of the brain: the midbrain (where the dopamine cell that are lost in Parkinson’s disease normal reside) and the striatum (where the dopamine cells release their dopamine). Six additional monkeys with induced Parkinson’s disease received saline as a control condition. Behavioural testing was conducted and the brains were inspected at 6 and 12 months.

When the brains were analysed at 12 months post surgery, the researchers found that less than 2% of the transplanted cells actually developed into dopamine neurons. While this is a very low number of dopamine neurons, of greater concern is that we don’t know what became of the remaining transplanted cells.

More disturbing, however, is that the authors noted extensive migration of the cells into other areas of the brain. They have also reported this phenomena in their previous study involving mice. This is represents a major concern regarding the move to the clinic. The goal of the surgery is to inject the cells into a specific region of the brain for a specific reason  – localised production of dopamine. The surgeons want the cells to stay where they are placed and for them to produce dopamine in that location. If cells are migrating away from that location and the dopamine is being produced in different areas of the brain, the therapeutic effect of the cell transplantation procedure may be reduced and there could also be unexpected side-effects (for example, dopamine being produced in the wrong areas of the brain – areas where dopamine should not be produced). Based on these findings, we still believe that proceeding to the clinic with these particular types of stem cells is premature and unwise.

ISCO is yet to make a press release about this overnight surgery (we can hopefully expect it later today given US time zones). The surgeons who conducted the surgery, however, have reiterated that this study is just a phase 1 trial to determine the safety of these cells in human. The transplanted subjects will be monitored for 12 months.

We will follow the proceedings here at the Science of Parkinson’s and keep you updated.


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 shares the concerns of the Parkinson’s scientific community that the research supporting the current Australian trial does not support the trial moving into the clinic. 

EDITORIAL NOTE – 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. 


The banner for today’s post is of a scan of a brain after surgery. Source: Bionews-tx

The debate surrounding a new Stem cell transplantation trial for Parkinson’s

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In December last year, the Australian government gave official clearance for an American company – International Stem Cell Corporation – to conduct a stem cell based clinical trial at the Royal Melbourne Hospital in Melbourne. This news was greeted with both excited hope from the Parkinson’s support community, but also concern from the Parkinson’s research community. In this post we will explore exactly what is going on.

Before reading on it may be wise for those unfamiliar with transplantation therapy in Parkinson’s disease to read our previous post about the topic, where we discuss the concept and the history of the field. Click here to read that post.


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On the 14th December, the ‘Therapeutics Goods Administration’ (TGA) of Australia passed a regulatory submission from International Stem Cell Corporation (ISCO) for its wholly owned subsidiary, Cyto Therapeutics, to conduct a Phase I/II clinical trial of human stem cell-derived neural cells in patients with moderate to severe Parkinson’s disease. The hospital where the trial will be conducted -the  Royal Melbourne Hospital in Melbourne – gave ethical approval in March this year for the trial to start and the company is now recruiting subjects.

What are the details of the trial?

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Cyto Therapeutics (the subsidiary of ISCO) is planning a Phase I/IIa clinical study. This will evaluate the safety of the technique and provide some preliminary efficacy results. They are going to transplant human parthenogenetic stem cells-derived neural stem cells (ISC-hpNSC, for an explanation of this, please see below) into the brains of 12 patients with moderate to severe Parkinson’s disease. The study will be:

  • an open-label (meaning that everyone knows what they are being treated with),
  • single center (Royal Melbourne Hospital in Melbourne),
  • uncontrolled (there wil be no sham/placebo treated group for comparison)
  • an evaluation of three different doses of neural cells (from 30,000,000 to 70,000,000)

Following the transplantation procedure, the patients will be monitored for 12 months at specified intervals, to evaluate the safety and biologic activity of ISC-hpNSC. The monitoring process will include various neurological assessments and brain scans (PET) performed at baseline (as part of the initial screening assessment), and at 6 and 12 months post surgery.

What are ISC-hpNSCs?

Transplantation of cells is theoretically a good way of replacing the tissue that is lost in neurodegenerative conditions, like Parkinson’s disease. Previous (and the current Transeuro) clinical trials have usually used tissue dissected from aborted fetuses to supply the dopamine neurons required for the transplantations. Obviously there are major ethic and moral issues/problems with this approach. There are also procedural issues with these trials (surgeries being cancelled as not enough tissue is available – tissue from at least three fetuses is required for each transplant).

Growing dopamine cells in petri dishes solves many of these problems. Millions of cells can be grown from a small number of starting cells, and there are no ethical issues regarding the fetal donors. As a result, there has been a major effort in the research community to push stem cells to become dopamine neurons that can be used in transplantation procedures.

Embryonic stem (ES) cells are of particular interest to researchers as a good starting point because the cells have the potential to become any type of cell in the body – they are ‘pluripotent’. ES cells can be encouraged using specific chemicals to become whatever kind of cell you want.

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Embryonic stem cells in a petridish. Source: Wikipedia

Embryonic stem cells are derived from a fertilized egg cell. The egg cell will divide, to become two cells, then four, eight, sixteen, etc. Gradually, it enters a stage called the ‘blastocyst’. Inside the blastocyst is a group of cell that are called the ‘inner stem cell mass’, and it is these cells that can be collected and used as ES cells.

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The process of attaining ES cells. Source: Howstuffworks

The human parthenogenetic stem cells-derived neural stem cells (hpNSC) that are going to be used in the Melbourne trial are slightly different. The hpNSCs come from an unfertilized egg – that is to say, no sperm cell is involved. The egg cell is chemically encouraged to start dividing and then becoming a blastocyst. This process is called ‘Parthenogenesis’, and it actually occurs naturally in some plants and animals.  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.

What has been the response to the announced trial?

In general, the response from the Parkinson’s community has been very positive. The announcement of the trial was greeted by numerous support groups as a positive step forward (for some examples see Parkinson’s UK and the stem cellar blog).

So why then is the research community concerned about the study?

Basically the research community is concerned that this trial will be a repeat of the infamous Colorado/Columbia Trial and Tampa Bay trial back in the 1990s (two double-blind studies which initially suggested no positive effect from transplantation). Both of these studies have been criticised for methodological flaws, but more importantly longer term follow-ups with patients have suggested that the period of observation was too short (12-24 months post transplant), and longer term the transplants have had more positive outcomes – the cells simply required a longer period of time to fully develop into mature neurons. This last detail is important when considering the new trial in Australia – the trial will only follow the subjects for a period of one year.

There are concerns that the absence of paternal genes in parthenogenic stem cells has not been thoroughly investigated (remember that these cells only have the genes from the female egg cell). Paternal genes are believed to be more dominant that female genes during development (Click here for more on this). They may play an important role in the development of dopamine neurons, but this has never been investigated. As a result, researchers are asking if it is wise to move to the clinic before such issues are addressed.

There is also concerns that the preclinical research supporting the trial from the companies involved (ISCO and Cyto Therapeutic) is lacking. While there has been some research into the use of parthenogenic stem cells in models of Parkinson’s (Click here for an example), the research from the company involved in this trial is limited to just a couple of peer-reviewed publications.

The research community has begun expressing their concerns in editorial comments in various journals – the most recent being in the Journal of Parkinson’s disease (Click here to read that article – it is open access).

What preclinical research is supporting the trial?

As far as we here at the SoPD are aware (and we would be very pleased to be corrected on this), there is one research article on the company website dealing with the production of dopamine neurons, and that study did not deal with transplantation. It simply described the recipe from making dopamine neurons.

SciRep-title

Title: Deriving dopaminergic neurons for clinical use. A practical approach.
Authors: Gonzalez R, Garitaonandia I, Abramihina T, Wambua GK, Ostrowska A, Brock M, Noskov A, Boscolo FS, Craw JS, Laurent LC, Snyder EY, Semechkin RA.
Journal: Sci Rep. 2013;3:1463.
PMID: 23492920                 (This article is OPEN ACCESS if you would like to read it)

(One important caveat here – the research published in this study was conducted using both embryonic stem cells (WA-09 cell line) and hpNSCs, but there is no indication in the text as to which cells were used for each result or whether the different types of pluripotent cells gave the same results. The text is unclear on this)

The company also published a study last year in which they transplanted the hpNSCs into both a rodent and primate model of Parkinson’s disease:

Gonzalez-title

Title: Proof of concept studies exploring the safety and functional activity of human parthenogenetic-derived neural stem cells for the treatment of Parkinson’s disease.
Authors: Gonzalez R, Garitaonandia I, Crain A, Poustovoitov M, Abramihina T, Noskov A, Jiang C, Morey R, Laurent LC, Elsworth JD, Snyder EY, Redmond DE Jr, Semechkin R.
Journal: Cell Transplant. 2015;24(4):681-90.
PMID: 25839189

The researchers in this study grew the hpNSCs in petridishes and pushed the cells towards becoming dopamine neurons, and then transplanted them into ten Parkinsonian rats and two Parkinsonian primates. Several months after transplantation, the researchers found the hpNSCs inside the brain and some of them had become dopamine neurons. There was, unfortunately, no indication as to how many of the hpNSCs survived the transplantation procedure. Nor any indication as to how many of them actually became dopamine neurons.

In addition, no behavioural data is presented in the study so there is no evidence that the cells had any functional effect. The researchers did measure the amount of dopamine in the brain, but those result suggested that there was only marginally more dopamine in the transplanted animals than the control animals (which had lesioned dopamine systems and saline injections rather than hpNSCs). Thus there is very evidence that the cells are functional inside the brain.

The researchers wrote in the report that “Most of the engrafted hpNSCs were dispersed from the graft site and remained undifferentiated”. This is not an ideal situation for a cell being transplanted into a particular region of the brain. Nor is it ideal for an undifferentiated cell to be going to the clinic.

And given that these two papers form the bulk of what has been published by the company with regards to their Parkinson’s disease work, researchers are concerned that the company is moving so aggressively to trial.

To be completely fair, ISCO has stated in a press release from April 2014, that their hpNSCs have been tested in 18 Parkinsonian primates. They suggested that those transplanted animals presented “significant improvement in the main Parkinson’s rating score”. Given that those results have never been made public, however, we are unclear as to what they actually mean (what is the “main Parkinson’s rating score”?).

 

We will follow the proceedings here at the Science of Parkinson’s with great interest.


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 review of the current situation, but ultimately 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. 

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. 


The header is of a scan of a brain after surgery. Source: Bionews-tx


UPDATE: 26/05/2016
ISCO has published further pre-clinical data this week regarding the cells that will be transplanted in their clinical trial. The data presented is from 18 transplanted monkeys:

Title: Neural Stem Cells Derived from Human Parthenogenetic Stem Cells Engraft and Promote Recovery in a Nonhuman Primate Model of Parkinson’s Disease.
Authors: Gonzalez R, Garitaonandia I, Poustovoitov M, Abramihina T, McEntire C, Culp B, Attwood J, Noskov A, Christiansen-Weber T, Khater M, Mora-Castilla S, To C, Crain A, Sherman G, Semechkin A, Laurent LC, Elsworth JD, Sladek J, Snyder EY, Jr DE, Kern RA.
Journal: Cell Transplant. 2016 May 20. [Epub ahead of print]
PMID: 27213850     (This article is OPEN ACCESS if you would like to read it)

In this study, 12 African Green monkeys with induced Parkinson’s disease (caused by the neurotoxin MPTP) were transplanted with hpNSCs in the midbrain and the striatum. 6 additional monkeys with induced Parkinson’s disease received saline as a control condition. Behavioural testing was conducted and the brains were inspected at 6 and 12 months.

Behaviourally, there was very little difference between the animals that were transplanted versus the control animals when they were compared at 12 months of age. This suggests that the transplant procedure is safe, but may not be having an effect at 12 months.

An inspection of the brain suggested that 10% of the transplanted cells survive to 12 months of age, and a few of them become dopamine neurons.

Some concerns regarding this new study:
Again the researchers have chosen to use saline injections as their control condition. It would be useful to see a comparison of hpNSCs with other types of transplanted cells (eg. fetal tissue or embryonic stem cells) – for a fairer comparison of efficiency.

The biochemical readings (the amount of dopamine in the brain) suggest an small increase in dopamine levels following transplantation, but only in one or two areas of the brain. Most of the analysed regions show no difference. And there is no comparison with a normal brain so it is difficult judge how truly restorative this procedure is. The increases that are observed may be minimal compared to what they should be in a normal brain.

Less than 2% of the transplanted cells became dopamine neurons. This is a bit of a worry given that we don’t know what the rest of the transplanted cells are doing. And the authors noted extensive migration of the cells into other areas of the brain. They reported this in their previous study. This is cause for real concern leading up to their clinical trial. The cells are being transplanted into a specific region of the brain for a specific reason (localised production of dopamine). If that dopamine is being produced in different areas of the brain, there may be unexpected side-effects from the procedure.

Another cause for concern leading up to the clinical trial is that the follow up period for the trial is only 12 months. Given that so little improvement has been seen in these monkeys over 12 months, how do the investigators expect to see significant changes in human over 12 months? The cells may well have an effect long term, but from the behavioural results presented in this new study, it is apparent that it will be extremely difficult to judge efficacy within 12 months.

Even when trying to view the study with an unbiased eye, it is difficult to agree with the researchers conclusion that the results “support the approval of the world’s first pluripotent stem cell based Phase I/IIa study for the treatment of Parkinson’s disease”. The lack of effect over 12 months and the migration of the transplanted cells suggest a serious rethink of the planned clinical study is required.