In my previous post, we briefly reviewed the results of the phase II double-blind, randomised clinical trial of Exenatide in Parkinson’s disease. The study indicates a statistically significant effect on motor symptom scores after being treated with the drug.
Over the last few days, there have been many discussions about the results, what they mean for the Parkinson’s community, and where things go from here, which have led to further questions.
In this post I would like to address several matters that have arisen which I did not discuss in the previous post, but that I believe are important.
I found out about the Exenatide announcement – via whispers online – on the afternoon of the release. And it was in a mad rush when I got home that night that I wrote up the post explaining what Exenatide is. I published the post the following evening however because I could not access the research report from home (seriously guys, biggest finding in a long time and it’s not OPEN ACCESS?!?!?) and I had to wait until I got to work the next day to actually view the publication.
I was not really happy with the rushed effort though and decided to follow up that post. In addition, there has been A LOT of discussion about the results over the weekend and I thought it might be good to bring aspects of those different discussion together here. The individual topics are listed below, in no particular order of importance:
1. Size of the effect
There are two considerations here.
Firstly, there have been many comments about the actual size of the effect in the results of the study itself. When people have taken a deeper look at the findings, they have come back with questions regarding those findings.
And second, there have also been some comments about the size of the effect that this result has already had on the Parkinson’s community, which has been considerable (and possibly disproportionate to the actual result).
The size of the effect in the results
The results of the study suggested that Exenatide had a positive effect on the motor-related symptoms of Parkinson’s over the course of the 60 week trial. This is what the published report says, it is also what all of the media headlines have said, and it sounds really great right?
The main point folks keep raising, however, is that the actual size of the positive effect is limited to just the motor features of Parkinson’s disease. If one ignores the Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores and focuses on the secondary measures, there isn’t much to talk about. In fact, there were no statistically significant differences in any of the secondary outcome measures. These included:
For many people diagnosed with Parkinson’s disease, one of the scariest prospects of the condition that they face is the possibility of developing dyskinesias.
Dyskinesias are involuntary movements that can develop after long term use of the primary treatment of Parkinson’s disease: Levodopa
In todays post I discuss one experimental strategy for dealing with this debilitating aspect of Parkinson’s disease.
Dyskinesia. Source: JAMA Neurology
There is a normal course of events with Parkinson’s disease (and yes, I am grossly generalising here).
First comes the shock of the diagnosis.
This is generally followed by the roller coaster of various emotions (including disbelief, sadness, anger, denial).
Then comes the period during which one will try to familiarise oneself with the condition (reading books, searching online, joining Facebook groups), and this usually leads to awareness of some of the realities of the condition.
One of those realities (especially for people with early onset Parkinson’s disease) are dyskinesias.
What are dyskinesias?
Dyskinesias (from Greek: dys – abnormal; and kinēsis – motion, movement) are simply a category of movement disorders that are characterised by involuntary muscle movements. And they are certainly not specific to Parkinson’s disease.
As I have suggested in the summary at the top, they are associated in Parkinson’s disease with long-term use of Levodopa (also known as Sinemet or Madopar).
Sinemet is Levodopa. Source: Drugs
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.
The image above presents a ‘before treatment’ (left) and ‘after treatment’ (right) brain scan image from a recent research report of a clinical study that looked at the use of Acetylcysteine (also known as N-acetylcysteine or simply NAC) in Parkinson’s disease.
DaTscan brain imaging technique allows us to look at the level of dopamine processing in an individual’s brain. Red areas representing a lot; blue areas – not so much. The image above represents a rather remarkable result and it certainly grabbed our attention here at the SoPD HQ (I have never seen anything like it!).
In today’s post, we will review the science behind this NAC and discuss what is happening with ongoing clinical trials.
Source: The Register
Let me ask you a personal question:
Have you ever overdosed on Paracetamol?
Regardless of your answer to that question, one of the main treatments for Paracetamol overdose is administration of a drug called ‘Acetylcysteine’.
Why are you telling me this?
Because acetylcysteine is currently being assessed as a potential treatment for Parkinson’s disease.
Oh I see. Tell me more. What is acetylcysteine?
Acetylcysteine. Source: Wikimedia
Acetylcysteine (N-acetylcysteine or NAC – commercially named Mucomyst) is a prodrug – that is a compound that undergoes a transformation when ingested by the body and then begins exhibiting pharmacological effects. Acetylcysteine serves as a prodrug to a protein called L-cysteine, and – just as L-dopa is an intermediate in the production of dopamine – L-cysteine is an intermediate in the production of another protein called glutathione.
Take home message: Acetylcysteine allows for increased production of Glutathione.
What is glutathione?
Glutathione. Source: Wikipedia
Glutathione (pronounced “gloota-thigh-own”) is a tripeptide (a string of three amino acids connected by peptide bonds) containing the amino acids glycine, glutamic acid, and cysteine. It is produced naturally in nearly all cells. In the brain, glutathione is concentrated in the helper cells (called astrocytes) and also in the branches of neurons, but not in the actual cell body of the neuron.
It functions as a potent antioxidant.
A new research report looking at the use of cholesterol-reducing drugs and the risk of developing Parkinson’s disease has just been published in the scientific journal Movement disorders.
The results of that study have led to some pretty startling headlines in the media, which have subsequently led to some pretty startled people who are currently taking the medication called statins.
In todays post, we will look at what statins are, what the study found, and discuss what it means for our understanding of Parkinson’s disease.
Cholesterol forming plaques (yellow) in the lining of arteries. Source: Healthguru
Cholesterol gets a lot of bad press.
Whether it’s high and low, the perfect balance of cholesterol in our blood seems to be critical to our overall health and sense of wellbeing. At least that is what we are constantly being told this by media and medical professionals alike.
But ask yourself this: Why? What exactly is cholesterol?
Good question. What is cholesterol?
Cholesterol (from the Greek ‘chole‘- bile and ‘stereos‘ – solid) is a waxy substance that is circulating our bodies. It is generated by the liver, but it is also found in many foods that we eat (for example, meats and egg yolks).
The chemical structure of Cholesterol. Source: Wikipedia
Cholesterol falls into one of three major classes of lipids – those three classes of lipids being Triglycerides, Phospholipids and Steroids (cholesterol is a steroid). Lipids are major components of the cell membranes and thus very important. Given that the name ‘lipids’ comes from the Greek lipos meaning fat, people often think of lipids simply as fats, but fats more accurately fall into just one class of lipids (Triglycerides).
Like many fats though, cholesterol dose not dissolve in water. As a result, it is transported within the blood system encased in a protein structure called a lipoprotein.
The structure of a lipoprotein; the purple C inside represents cholesterol. Source: Wikipedia
Lipoproteins have a very simple classification system based on their density:
- very low density lipoprotein (VLDL)
- low density lipoprotein (LDL)
- intermediate density lipoprotein (IDL)
- high density lipoprotein (HDL).
Now understand that all of these different types of lipoproteins contain cholesterol, but they are carrying it to different locations and this is why some of these are referred to as good and bad.
The first three types of lipoproteins carry newly synthesised cholesterol from the liver to various parts of the body, and thus too much of this activity would be bad as it results in an over supply of cholesterol clogging up different areas, such as the arteries.
LDLs, in particular, carry a lot of cholesterol (with approximately 50% of their contents being cholesterol, compared to only 20-30% in the other lipoproteins), and this is why LDLs are often referred to as ‘bad cholesterol’. High levels of LDLs can result in atherosclerosis (or the build-up of fatty material inside your arteries).
Progressive and painless, atherosclerosis develops as cholesterol silently and slowly accumulates in the wall of the artery, in clumps that are called plaques. White blood cells stream in to digest the LDL cholesterol, but over many years the toxic mess of cholesterol and cells becomes an ever enlarging plaque. If the plaque ever ruptures, it could cause clotting which would lead to a heart attack or stroke.
So yeah, some lipoproteins can be considered bad.
HDLs, on the other hand, collects cholesterol and other lipids from cells around the body and take them back to the liver. And this is why HDLs are sometimes referred to as “good cholesterol” because higher concentrations of HDLs are associated with lower rates of atherosclerosis progression (and hopefully regression).
But why is cholesterol important?
While cholesterol is usually associated with what is floating around in your bloodstream, it is also present (and very necessary) in every cell in your body. It helps to produce cell membranes, hormones, vitamin D, and the bile acids that help you digest fat.
It is particularly important for your brain, which contains approximately 25 percent of the cholesterol in your body. Numerous neurodegenerative conditions are associated with cholesterol disfunction (such as Alzheimer’s disease and Huntington’s disease – Click here for more on this). In addition, low levels of cholesterol is associated with violent behaviour (Click here to read more about this).
Are there any associations between cholesterol and Parkinson’s disease?
The associations between cholesterol and Parkinson’s disease is a topic of much debate. While there have been numerous studies investigating cholesterol levels in blood in people with Parkinson’s disease, the results have not been consistent (Click here for a good review on this topic).
Rather than looking at cholesterol directly, a lot of researchers have chosen to focus on the medication that is used to treat high levels of cholesterol – a class of drugs called statins.
Title: Prospective study of statin use and risk of Parkinson disease.
Authors: Gao X, Simon KC, Schwarzschild MA, Ascherio A.
Journal: Arch Neurol. 2012 Mar;69(3):380-4.
PMID: 22410446 (This article is OPEN ACCESS if you would like to read it)
In this study the researchers conduced a prospective study involving the medical details of 38 192 men and 90 874 women from two huge US databases: the Nurses’ Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS).
NHS study was started in 1976 when 121,700 female registered nurses (aged 30 to 55 years) completed a mailed questionnaire. They provided an overview of their medical histories and health-related behaviours. The HPFS study was established in 1986, when 51,529 male health professionals (40 to 75 years) responded to a similar questionnaire. Both the NHS and the HPFS send out follow-up questionnaires every 2 years.
By analysing all of that data, the investigators found 644 cases of Parkinson’s disease (338 women and 306 men). They noticed that the risk of Parkinson’s disease was approximately 25% lower among people currently taking statins when compared to people not using statins. And this association was significant in statin users younger than 60 years of age (P = 0.02).
What are statins?
Also known as HMG-CoA reductase inhibitors, statins are a class of drug that inhibits/blocks an enzyme called 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase.
HMG-CoA reductase is the key enzyme regulating the production of cholesterol from mevalonic acid in the liver. By blocking this process statins help lower the total amount of cholesterol available in your bloodstream.
Statins are used to treat hypercholesterolemia (also called dyslipidemia) which is high levels of cholesterol in the blood. And they are one of the most widely prescribed classes of drugs currently available, with approximately 23 percent of adults in the US report using statin medications (Source).
Now, while the study above found an interesting association between statin use and a lower risk of Parkinson’s disease, the other research published on this topic has not been very consistent. In fact, a review in 2009 found a significant associations between statin use and lower risk of Parkinson’s disease was observed in only two out of five prospective studies (Click here to see that review).
New research published this week has attempted to clear up some of that inconsistency, by starting with a huge dataset and digging deep into the numbers.
So what new research has been published?
Title: Statins may facilitate Parkinson’s disease: Insight gained from a large, national claims database
Authors: Liu GD, Sterling NW, Kong L, Lewis MM, Mailman RB, Chen H, Leslie D, Huang X
Journal: Movement Disorder, 2017 Jun;32(6):913-917.
Using the MarketScan Commercial Claims and Encounters database which catalogues the healthcare use and medical expenditures of more than 50 million employees and their family members each year, the researcher behind that study identified 30,343,035 individuals that fit their initial criteria (that being “all individuals in the database who had 1 year or more of continuous enrolment during January 1, 2008, to December 31, 2012, and were 40 years of age or older at any time during their enrolment”). From this group, the researcher found a total of 21,599 individuals who had been diagnosed with Parkinson’s disease.
In their initial analysis, the researchers found that Parkinson’s disease was positively associated with age, male gender, hypertension, coronary artery disease, and usage of cholesterol-lowering drugs (both statins and non-statins). The condition was negatively associated with hyperlipidemia (or high levels of cholesterol). This result suggests not only that people with higher levels of cholesterol have a reduced chance of developing Parkinson’s disease, but taking medication to lower cholesterol levels may actually increase ones risk of developing the condition.
One interesting finding in the data was the effect that different types of statins had on the association.
Statins can be classified into two basic groups: water soluble (or hydrophilic) and lipid soluble (or lipophilic) statins. Hydrophilic molecule have more favourable interactions with water than with oil, and vice versa for lipophilic molecules.
Hydrophilic vs lipophilic molecules. Source: Riken
Water soluble (Hydrophilic) statins include statins such as pravastatin and rosuvastatin; while all other available statins (eg. atorvastatin, cerivastatin, fluvastatin, lovastatin and simvastatin) are lipophilic.
In this new study, the researchers found that the association between statin use and increased risk of developing Parkinson’s disease was more pronounced for lipophilic statins (a statistically significant 58% increase – P < 0.0001), compared to hydrophilic statins (a non-significant 19% increase – P = 0.25). One possible explanation for this difference is that lipophilic statins (like simvastatin and atorvastatin) cross the blood-brain barrier more easily and may have more effect on the brain than hydrophilic ones.
The investigators also found that this association was most robust during the initial phase of statin treatment. That is to say, the researchers observed a 82% in risk of PD within 1 year of having started statin treatment, and only a 37% increase five years after starting statin treatment.; P < 0.0001). Given this finding, the investigators questioned whether statins may be playing a facilitatory role in the development of Parkinson’s disease – for example, statins may be “unmasking” the condition during its earliest stages.
So statins are bad then?
Can I answer this question with a diplomatic “I don’t know”?
It is difficult to really answer that question based on the results of just this one study. This is mostly because this new finding is in complete contrast to a lot of experimental research over the last few years which has shown statins to be neuroprotective in many models of Parkinson’s disease. Studies such as this one:
Title: Simvastatin inhibits the activation of p21ras and prevents the loss of dopaminergic neurons in a mouse model of Parkinson’s disease.
Authors: Ghosh A, Roy A, Matras J, Brahmachari S, Gendelman HE, Pahan K.
Journal: J Neurosci. 2009 Oct 28;29(43):13543-56.
PMID: 19864567 (This study is OPEN ACCESS if you would like to read it)
In this study, the researchers found that two statins (pravastatin and simvastatin – one hydrophilic and one lipophilic, respectively) both exhibited the ability to suppress the response of helper cells in the brain (called microglial) in a neurotoxin model of Parkinson’s disease. This microglial suppression resulted in a significant neuroprotective effect on the dopamine neurons in these animals.
Another study found more Parkinson’s disease relevant effects from statin treatment:
TItle: Lovastatin ameliorates alpha-synuclein accumulation and oxidation in transgenic mouse models of alpha-synucleinopathies.
Authors: Koob AO, Ubhi K, Paulsson JF, Kelly J, Rockenstein E, Mante M, Adame A, Masliah E.
Journal: Exp Neurol. 2010 Feb;221(2):267-74.
PMID: 19944097 (This study is OPEN ACCESS if you would like to read it)
In this study, the researchers treated two different types of genetically engineered mice (both sets of mice produce very high levels of alpha synuclein – the protein closely associated with Parkinson’s disease) with a statin called lovastatin. In both groups of alpha synuclein producing mice, lovastatin treatment resulted in significant reductions in the levels of cholesterol in their blood when compared to the saline-treated control mice. The treated mice also demonstrated a significant reduction in levels of alpha synuclein clustering (or aggregation) in the brain than untreated mice, and this reduction in alpha synuclein accumulation was associated with a lessening of pathological damage in the brain.
So statins may not be all bad?
One thing many of these studies fail to do is differentiate between whether statins are causing the trouble (or benefit) directly or whether simply lowering cholesterol levels is having a negative impact. That is to say, do statins actually do something else? Other than lowering cholesterol levels, are statins having additional activities that could cause good or bad things to happen?
The recently published study we are reviewing in this post suggested that non-statin cholesterol medication is also positively associated with developing Parkinson’s disease. Thus it may be that statins are not bad, but rather the lowering of cholesterol levels that is. This raises the question of whether high levels of cholesterol are delaying the onset of Parkinson’s disease, and one can only wonder what a cholesterol-based process might be able to tell us about the development of Parkinson’s disease.
If the findings of this latest study are convincingly replicated by other groups, however, we may need to reconsider the use of statins not in our day-to-day clinical practice. At the very least, we will need to predetermine which individuals may be more susceptible to developing Parkinson’s disease following the initiation of statin treatment. It would actually be very interesting to go back to the original data set of this new study and investigate what addition medical features were shared between the people that developed Parkinson’s disease after starting statin treatment. For example, were they all glucose intolerant? One would hope that the investigators are currently doing this.
Are Statins currently being tested in the clinic for Parkinson’s disease?
(Oh boy! Tough question) Yes, they are.
There is currently a nation wide study being conducted in the UK called PD STAT.
Is this dangerous given the results of the new research study?
(Oh boy! Even tougher question!)
Again, we are asking this question based on the results of one recent study. Replication with independent databases is required before definitive conclusions can be made.
There have, however, been previous clinical studies of statins in neurodegenerative conditions and these drugs have not exhibited any negative effects (that I am aware of). In fact, a clinical trial for multiple sclerosis published in 2014 indicated some positive results for sufferers taking simvastatin:
Title: Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial.
Authors: Chataway J, Schuerer N, Alsanousi A, Chan D, MacManus D, Hunter K, Anderson V, Bangham CR, Clegg S, Nielsen C, Fox NC, Wilkie D, Nicholas JM, Calder VL, Greenwood J, Frost C, Nicholas R.
Journal: Lancet. 2014 Jun 28;383(9936):2213-21.
PMID: 24655729 (This article is OPEN ACCESS if you would like to read it)
In this double-blind clinical study (meaning that both the investigators and the subjects in the study were unaware of which treatment was being administered), 140 people with multiple sclerosis were randomly assigned to receive either the statin drug simvastatin (70 people; 40 mg per day for the first month and then 80 mg per day for the remainder of 18 months) or a placebo treatment (70 people).
Patients were seen at 1, 6, 12, and 24 months into the study, with telephone follow-up at months 3 and 18. MRI brain scans were also made at the start of the trial, and then again at 12 months and 25 months for comparative sake.
The results of the study indicate that high-dose simvastatin was well tolerated and reduced the rate of whole-brain shrinkage compared with the placebo treatment. The mean annualised shrinkage rate was significantly lower in patients in the simvastatin group. The researchers were very pleased with this result and are looking to conduct a larger phase III clinical trial.
Other studies have not demonstrated beneficial results from statin treatment, but they have also not observed a worsening of the disease conditions:
Title: A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease.
Authors:Sano M, Bell KL, Galasko D, Galvin JE, Thomas RG, van Dyck CH, Aisen PS.
Journal: Neurology. 2011 Aug 9;77(6):556-63.
PMID: 21795660 (This article is OPEN ACCESS if you would like to read it)
In this study, the investigators recruited a total of 406 individuals were mild to moderate Alzheimer’s disease, and they were randomly assigned to two groups: 204 to simvastatin (20 mg/day, for 6 weeks then 40 mg per day for the remainder of 18 months) and 202 to placebo control treatment. While Simvastatin displayed no beneficial effects on the progression of symptoms in treated individuals with mild to moderate Alzheimer’s disease (other than significantly lowering of cholesterol levels), the treatment also exhibited no effect on worsening the disease.
So what does it all mean?
Research investigating cholesterol and its association with Parkinson’s disease has been going on for a long time. This week a research report involving a huge database was published which indicated that using cholesterol reducing medication could significantly increase one’s risk of developing Parkinson’s disease.
These results do not mean that someone being administered statins is automatically going to develop Parkinson’s disease, but – if the results are replicated – it may need to be something that physicians should consider before prescribing this class of drug.
Whether ongoing clinical trials of statins and Parkinson’s disease should be reconsidered is a subject for debate well above my pay grade (and only if the current results are replicated independently). It could be that statin treatment (or lowering of cholesterol) may have an ‘unmasking’ effect in some individuals, but does this mean that any beneficial effects in other individuals should be discounted? If preclinical data is correct, for example, statins may reduce alpha synuclein clustering in some people which could be beneficial in Parkinson’s.
As we have said above, further research is required in this area before definitive conclusions can be made. This is particularly important given the inconsistencies of the previous research results in the statin and Parkinson’s disease field of investigation.
EDITORIAL NOTE: The information provided by the SoPD website is for information and educational purposes only. Under no circumstances should it ever be considered medical or actionable advice. It is provided by research scientists, not medical practitioners. Any actions taken – based on what has been read on the website – are the sole responsibility of the reader. Any actions being contemplated by readers should firstly be discussed with a qualified healthcare professional who is aware of your medical history. While some of the information discussed in this post may cause concern, please speak with your medical physician before attempting any change in an existing treatment regime.
The banner for today’s post was sourced from HarvardHealth
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
A major trend in experimental medicine at present is ‘immunotherapy‘ – stimulating or reprogramming the immune system to help fight particular diseases.
A research group in Nebraska have attempted to use this approach for Parkinson’s disease, and recently they have published some very interesting clinical trial results.
In today’s post, we will discuss the science and review the results of their research.
Nebraska. Source: The Toast
Here at the SoPD HQ, we like surprises.
And when several readers contacted us about some interesting results from a new clinical trial for Parkinson’s disease that we knew nothing about, we were rather ‘OMG! What a fantastic surprise!’ about it.
The results stem from a clinical trial that has taken a rather different approach to tackling Parkinson’s disease: boosting the immune system to help fight off the condition. And rather than simply covering up the symptoms, the drug being tested may actually slow down the condition.
You may have heard about this trial as the results of this clinical study have attracted the attention of the media:
So what was the new clinical trial all about?
Let’s start with the context of the study. You see, it took place in the great US state of Nebraska.
Interesting place Nebraska.
Nebraska (in red). Source: Wikipedia
And home to the largest porch swing in the world (holds 18 adults or 24 children – amazing).
The world’s largest swing chair. Source: Pinterest
Nebraska is also one of the top agricultural states in the USA, with about 93% of the land being used for farming. And approximately 40% of the state’s population (750,000 out of 1.8 million) lives in those rural areas. As a result of this largely rural population, there are probably a lot of people in Nebraska being exposed to pesticide and insecticides (in the air they breath and the water they drink).
This exposure is believed to be one of the reasons why Nebraska has one of the highest rates of Parkinson’s disease in the USA.
There are approximately 330 people per 100,000 of the general population living with Parkinson’s Disease in Nebraska (Click here for more on this). Compare that with just 180 people per 100,000 of the UK general population having Parkinson’s Disease (Click here for more on this).
As a result of this statistic, Parkinson’s disease is taken very seriously in Nebraska.
There is also a lot of Parkinson’s disease research being conducted there.
And this brings us to the clinical study results we are going to discuss:
Title:Evaluation of the safety and immunomodulatory effects of sargramostim in a randomized, double-blind phase 1 clinical Parkinson’s disease trial
Authors: Gendelman HE, Zhang Y, Santamaria P, Olson KE, Schutt CR, Bhatti D, Shetty BLD, Lu Y, Estes KA, Standaert DG, Heinrichs-Graham E, Larson L, Meza JL, Follett M, Forsberg E, Siuzdak G, Wilson TW, Peterson C, & Mosley RL
Journal: npj Parkinson’s Disease (2017) 3, 10.
PMID: N/A (This article is OPEN ACCESS if you would like to read it)
For this randomised, double-blind phase 1 clinical trial, the researchers enrolled 20 people with Parkinson’s disease and 17 age-matched non-Parkinsonian control subjects. The people with Parkinson’s disease ranged in age from 53 to 76 years (mean age of 64) and they had had symptoms for 3–14 years (the mean was 7 years). Both the Parkinson’s disease group and control group were monitored for 2 months before the trial started in order to establish baseline measurements and profiles.
The Parkinson’s disease group were then randomly assigned into two equal sized groups (10 subjects each) and they were then self-administered (by self-injection) either sargramostim (6 μg/kg/day) or a placebo control solution (saline) for 56 days (click here to see the details of the clinical trial).
Hang on a second, what is Sargramostim?
Sargramostim (marketed by the pharmaceutical company Genzyme under the tradename ‘Leukine’) is an Food and Drug Administration (FDA) -approved recombinant granulocyte macrophage colony-stimulating factor (GM-CSF) that functions as an immunostimulator.
What…on earth…..does any of that….actually mean?
Ok, so Food and Drug Administration (FDA) -approved means that this drug is safe to use in humans. Sargramostim is currently widely used in bone marrow transplantation procedures, to stimulate the production of new blood cells.
‘Recombinant‘ basically means that we are talking about an artificially produced protein.
‘Granulocyte macrophage colony-stimulating factor‘ is an actual protein that our bodies produce. GM-CSF is a small protein that is secreted by various types of cells in our body, and it functions as a cytokine. And yes, I know what you are going to ask:
What’s a cytokine?
Cytokines (from the Greek: kýtos meaning ‘container, body, cell’; and kī́nēsis meaning ‘movement’) are small proteins that are secreted by certain cells in the body and they have an effect on other cells. Cytokines are a method of communication for cells.
How cytokines work. Source: SBS
Granulocyte macrophage colony-stimulating factor is secreted by various cells around the body to communicate with the immune system that something is wrong. In it’s actually function, GM-CSF acts as a white blood cell growth factor, or a stimulant of white blood cell production.
GM-CSF stimulates blood stem cells into production. Source: Oxymed
Why are white blood cells important?
While red blood cells are principally involved with the delivery of oxygen to the various parts of the body, the white blood cells (also referred to as leukocytes or leucocytes), are the cells of your immune system that protect your body against both infectious disease and foreign invaders.
6 types of white blood cells. Source: Stfranciscare
GM-CSF stimulates blood stem cells to produce more neutrophils, eosinophils, basophils, and monocytes (all types of white blood cells – see image above). Monocytes then migrate towards the tissue affected by the injury or disease, where they then mature into macrophages and dendritic cells (Macrophages are large, specialised cells that are responsible for removing damaged target cells).
Once at the site of trouble, macrophages produce pro-inflammatory neurotoxins that help to destroy unhealthy or damaged cells, making them easier to engulf and dispose of. The problem is that those released neurotoxins can also damage surrounding healthy cells.
Given that GM-CSF stimulates this kind of activity, you are probably wondering why researchers would be giving Sargramostim to folks with Parkinson’s disease.
But GM-CSF also does something else that is really interesting:
GM-CSF stimulates regulatory T (Treg) cells.
What are regulatory T cells?
Regulatory T (Treg) cells maintain order in the immune system. They do this by enforcing a dominant negative regulation on other immune cells, particularly other T-cells.
T-cells are a type of white blood cell that circulate around our bodies, scanning for cellular abnormalities and infections.
Think of T-cells as the inquisitive neighbours curious about and snooping around a local crime scene, and then imagine that Treg cells are the police telling them “nothing to see here, move along”.
Tregs maintaining order. Source: Keywordsuggestions
Treg cells are particularly important for calming down effector T cells (or T-eff cells). These are several different types of T cell types that ‘actively’ respond to a stimulus. They include:
- Helper T cells (TH cells) which assist other white blood cells in the immunological process
- Killer T cells which destroy virus-infected cells, tumor cells, and are involve in transplant rejection.
The normal situation in the body is to have a balance between T-eff cells and Treg cells. If there are too many T-eff cells, there is increased chances of autoimmunity – or the immune system attacking healthy cells.
A delicate balance between healthy and autoimmune disease. Source: Researchgate
Too many Treg cells is not a good situation either, however, as they would leave the immune system suppressed and individuals vulnerable to disease.
How are Treg cells involved with Parkinson’s disease?
So, in Parkinson’s disease, researchers believe that the build up of the Parkinson’s associated protein, alpha synuclein may be toxic and killing certain cells in the brain (such as the dopamine neurons). When the cell dies and the alpha synuclein is released into the surrounding environment of the brain, it most likely does two things:
- irritates and activates the resident immune cells, called microglia
- activates the wider immune system, resulting in T-cell infiltration of the brain
The T-cells snoop around, detect that something isn’t quite right and then release their own cytokines which further activates the microglia. The microglia then release pro-inflammatory toxic chemicals which indiscriminately damage the unhealthy and healthy cells in the local area.
A.) The normal situation in PD; B.) the situation after GM-CSF treatment. Source: NCBI
Now the hypothesis is that GM-CSF may be able mediate this degenerative cycle by stimulating the induction of Treg cells, which can calm the activated microglia down, return it to a resting state and the healthy surrounding neurons survive intact.
Is there any research evidence for this effect in models of Parkinson’s disease?
Yes there is.
The group in Nebraska have actually been working ‘pre-clinically’ on this idea for some time:
Title: Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model ofParkinson’s disease.
Authors: Reynolds AD, Banerjee R, Liu J, Gendelman HE, Mosley RL.
Journal: J Leukoc Biol. 2007 Nov;82(5):1083-94.
In this study, the researchers demonstrated that by increasing the number of activated Treg cells in neurotoxin (MPTP)-injected mice, they could produce a greater than 90% level of protection of the dopamine neurons when compared to mice that did not receive the increase of Treg cells.
The Treg cells were found to mediate this neuroprotection through suppression of the microglial response to the neurotoxin. The investigators concluded that their data strongly supported the use of immunomodulation as a strategy for treating Parkinson’s.
They next extended these findings by looking at whether GM-CSF could provide neuroprotection in the same model of Parkinson’s disease:
Title: GM-CSF induces neuroprotective and anti-inflammatory responses in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxicated mice.
Authors: Kosloski LM, Kosmacek EA, Olson KE, Mosley RL, Gendelman HE.
Journal: J Neuroimmunol. 2013 Dec 15;265(1-2):1-10.
PMID: 24210793 (This article is OPEN ACCESS if you would like to read it)
In this study, the researchers gave GM-CSF prior to the neurotoxin (MPTP) which kills dopamine neurons. GM-CSF freely cross the blood-brain barrier which inhibits a lot of other drugs from entering the brain. This treatment protected the dopamine neurons and the investigators found increased Treg induction and reduced activation of the microglia cells.
This neuroprotective effect could also transferred between animals. Treg cells from GM-CSF treated mice were transferred to MPTP-treated mice and neuroprotection of the dopamine neurons was observed in those animals. The researchers concluded that the results provide evidence that GM-CSF modulation of the immune system could be of clinical benefit for people with Parkinson’s disease.
And they are not the only investigators who have demonstrated this. In addition to the work produced by the Nebraskan research team, other research groups have also observed beneficial effects of GM-CSF in models of Parkinson’s disease (Click here, here and here to read some of those reports).
In fact, for a very good OPEN ACCESS review on the topic of immunomodulation for Parkinson’s disease – click here.
And with all of this research backing them, the team in Nebraska decided to move GM-CSF towards the clinic with a small phase I clinical trial.
The Nebraska team: Dr Howard Gendelman, Dr Pamela Santamaria & Prof R. Lee Mosley. Source: Omaha
What did they find in the clinical trial?
In their randomized, double-blind, phase 1 clinical trial of 20 people with Parkinson’s disease taking either sargramostim (10 subjects) or a placebo control solution (10 subjects) for 56 days, the researchers found that Sargramostim firstly increases the the induction of Treg cells, and mediated suppression of the immune cells
More importantly, the sargramostim treated group demonstrated a modest improvement in their motor performance scores after 6 and 8 weeks of treatment when compared with the placebo group. The study was not large enough in size or duration for robust conclusions to be made, but the deviation between the two groups in motor scores in intriguing. This is particularly curious given that the sargramostim treatment group returned to a similar level of performance as the control (placebo) group at the 8 week assessment when they were no longer on sargramostim:
Change in motor scores of the participants. Source: Nature
One of the interesting features of this study was that the participants were a mixed bunch with regards to their Parkinson’s disease. The participants ranged in age from 53 to 76 years (mean age of 64) and they had had symptoms for 3–14 years (the mean was 7 years). It would be interesting to know (in a larger study) if there is any difference in the effect of this treatment based on length of time since diagnosis.
Another interesting aspect of the study is that it was double-blind. It is rather rare for a phase I clinical study to be double-blind, as they are usually just testing safety and tolerance. But given that sargramostim is used in the clinic already, the investigators had more flexibility with the study design. The double blind nature of the results only makes the findings more intriguing though.
The next step in this research is to plan a larger clinical study in 1-2 years time. The delay is caused by the desire for that trial to focus on an oral tablet (currently Sargramostim is only administered via an injection – not a popular route!). Those follow up studies will require groups taking different doses of the drug to get a better idea of effective dosages.
So what does it all mean?
Artificial modulation of the immune system represents tremendous opportunities for not only Parkinson’s disease, but also other conditions such as Alzheimer’s disease and amyotrophic lateral sclerosis. Recently, some researchers have concluded a clinical study of immunomodulation for Parkinson’s disease after almost 20 years of preclinical experimentation. The results are very interesting and may provide us with a novel method of treating the condition.
We here at the SoPD will be interested to see if Sargramostim makes it through the clinical testing process alone (as a “mono-therapy”) for Parkinson’s disease, or whether it will be used in combination with other drugs. One potential issue for this approach is that it leaves the individual with a suppressed immune system to defend them against other infectious agents.
Having said that, the fact that this approach may work could also tell us a great deal about the nature of Parkinson’s disease itself, and raising the idea that the body’s immune response could be involved with the progression of this neurodegenerative condition. We already know from several studies that certain anti-inflammation drugs (particularly Ibuprofen) can help to lower the risk of developing Parkinson’s disease (Click here for more on Ibuprofen).
Perhaps while we wait for the pill version of Sargramostim, a separate Ibuprofen study could be conducted to determine if this drug could slow down the progression of the disease.
The banner for today’s post was sourced from Diamond
‘Prana’ is a Hindu Sanskrit word meaning “life force”.
An Australian biotech company has chosen this word for their name.
Recently Prana Biotechnology Ltd announced some exciting results from their Parkinson’s disease research programme.
In today’s post we will look at what the company is doing, the science underlying the business plan, and review the results they have so far.
At the end of March, over 3000 researchers in the field of neurodegeneration gathered in the Austrian capital of Vienna for the 13th International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders (also known as ADPD2017).
The Vienna city hall. Source: EUtourists
A lot of interesting new research in the field of Parkinson’s disease was presented at the conference (we will look at some other presentation in future posts), but one was of particular interest to us here at SoPD HQ.
The poster entitled: ‘Abstract: 104 – PBT434 prevents neuronal loss, motor function and cognitive impairment in preclinical models of movement disorders by modulation of intracellular iron’, was presented by Associate Professor David Finkelstein, of the Florey Institute of Neuroscience and Mental Health (Melbourne, Australia).
Unfortunately the ADPD2017 conference’s scientific programme search engine does not allow for individual abstracts to be linked to on the web so if you would like to read the abstract, you will need to click here for the search engine page and search for ‘PBT434’ or ‘Finkelstein’ in the appropriate boxes.
Prof Finkelstein was presenting preclinical research that had been conducted by an Australian biotech company called Prana Biotechnology Ltd.
Source: Prana Biotechnology Ltd
What does the company do?
Prana Biotechnology Ltd has a large portfolio of over 1000 small chemical agents that they have termed ‘MPACs’ (or Metal Protein Attenuating Compounds). These compounds are designed to interrupt the interactions between particular metals and target proteins in the brain. The goal of this interruption is to prevent deterioration of brain cells in neurodegenerative conditions.
For Parkinson’s disease, the company is proposing a particular iron chelator they have called PBT434.
What is an iron chelator?
Iron chelator therapy involves the removal of excess iron from the body with special drugs. Chelate is from the Greek word ‘chela’ meaning “claw”.
Chelator therapy. Source: Stanford
Iron overload in the body is a common medical problem, sometimes arising from disorders of increased iron absorption such as hereditary haemochromatosis. Iron chelator therapy represents one method of reducing the levels of iron in the body.
But why is iron overload a problem?
Iron. Source: GlobalSpec
Good question. It involves the basic properties of iron.
Iron is a chemical element (symbol Fe). It has the atomic number 26 and by mass it is the most common element on Earth (it makes up much of Earth’s outer and inner core). It is absolutely essential for cellular life on this planet as it is involved with the interactions between proteins and enzymes, critical in the transport of oxygen, and required for the regulation of cell growth and differentiation.
So why then – as Rosalind asked in Shakespeare’s As You Like It – “can one desire too much of a good thing?”
Well, if you think back to high school chemistry class you may recall that there are these things called electrons. And if you have a really good memory, you will recall that the chemical hydrogen has one electron, while iron has 26 (hence the atomic number 26).
The electrons of iron and hydrogen. Source: Hypertonicblog
Iron has a really interesting property: it has the ability to either donate or take electrons. And this ability to mediate electron transfer is one of the reasons why iron is so important in the body.
Iron’s ability to donate and accept electrons means that when there is a lot of iron present it can inadvertently cause the production of free radicals. We have previously discussed free radicals (Click here for that post), but basically a free radical is an unstable molecule – unstable because they are missing electrons.
How free radicals and antioxidants work. Source: h2miraclewater
In an unstable format, free radicals bounce all over the place, reacting quickly with other molecules, trying to capture the much needed electron to re-gain stability. Free radicals will literally attack the nearest stable molecule, to steal an electron. This leads to the “attacked” molecule becoming a free radical itself, and thus a chain reaction is started. Inside a living cell this can cause terrible damage, ultimately killing the cell.
Antioxidants can help try and restore the balance, but in the case of iron overload iron doctors will prescribe chelator treatment to deal with the situation more efficiently. By soaking up excess iron, we can limit the amount of damage caused by the surplus of iron.
So what research has been done regarding iron content and the Parkinsonian brain?
Actually, quite a lot.
In 1968, Dr Kenneth Earle used an X-ray based technique to examine the amount of iron in the substantia nigra of people with Parkinson’s disease (Source). The substantial nigra is one of the regions in the brain most badly damaged by the condition – it is where most of the brain’s dopamine neurones resided.
The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source:Memorangapp
Earle examined 11 samples and compared them to unknown number of control samples and his results were a little startling:
The concentration of iron in Parkinsonian samples was two times higher than that of the control samples.
Since that first study, approximately 30 investigations have been made into levels of iron in the Parkinsonian brain. Eleven of those studies have replicated the Earle study by looking at postmortem tissue. They have used different techniques and the results have varied somewhat:
- Sofic et al. (1988) 1.8x increase in iron levels
- Dexter et al. (1989) 1.3x increase in iron levels
- Uitti et al. (1989) 1.1x increase in iron levels
- Riederer et al 1989 1.3x increase in iron levels
- Griffiths and Crossman (1993) 2.0x increase in iron levels
- Mann et al. (1994) 1.6x increase in iron levels
- Loeffler et al. (1995) 0.9 (lower)
- Galazka-Friedman et al., 1996 1.0 (no difference)
- Wypijewska et al. (2010) 1.0 (no difference)
- Visanji et al, 2013 1.7x increase in iron levels
Overall, however, there does appear to be a trend in the direction of higher levels of iron in the Parkinsonian brains. A recent meta-analysis of all this data confirmed this assessment as well as noting an increase in the caudate putamen (the region of the brain where the dopamine neuron branches release their dopamine – Click here for that study).
Brain imaging of iron (using transcranial sonography and magnetic resonance imaging (MRI)) has also demonstrated a strong correlation between iron levels in the substantia nigra region and Parkinson’s disease severity/duration (Click here and here to read more on this).
Thus, there appears to be an increase of iron in the regions most affected by Parkinson’s disease and this finding has lead researchers to ask whether reducing this increase in iron may help in the treatment of Parkinson’s disease.
How could iron overload be bad in Parkinson’s disease?
Well in addition to causing the production of free radicals, there are many possible ways in which iron accumulation could be aggravating cell loss in Parkinson’s disease.
Possible causes and consequences of iron overload in Parkinson’s disease. Source: Hindawi
High levels of iron can cause the oxidation of dopamine, which results in the production of hydrogen peroxide (H2O2 – a reactive oxygen species – the stuff that is used to bleach hair and is also used as a propellant in rocketry!). This reaction can cause further oxidative stress that can then lead to a range of consequences including protein misfolding, lipid peroxidation (which can cause the accumulation of the Parkinson’s associated protein alpha synuclein), mitochondrial dysfunction, and activation of immune cells in the brain.
And this is just a taster of the consequences.
Ok, so iron overload is bad, but what was the research presented in Austria?
Title: PBT434 prevents neuronal loss, motor function and cognitive impairment in preclinical models of movement disorders by modulation of intracellular iron
Authors: D. Finkelstein, P. Adlard, E. Gautier, J. Parsons, P. Huggins, K. Barnham, R. Cherny
Location: C01.a Posters – Theme C – Alpha-Synucleinopathies
The researchers at Prana Biotechnology Ltd assessed the potential of one of their candidate drugs, PBT434, in both cell culture and animal models of Parkinson’s disease. The PBT434 drug was selected for further investigation based on its performance in cell culture assays designed to test the inhibition of oxidative stress and iron-mediated aggregation of Parkinson’s associated proteins like alpha synuclein.
PBT434 significantly reduced the accumulation of alpha synuclein and markers of oxidative stress, and prevented neuronal loss.
The investigators also demonstrated that orally administered PBT434 readily crossed the blood brain barrier and entered the brain. In addition the drug was well-tolerated in the experimental animals and improved motor function in toxin-induced (MPTP and 6-hydroxydopamine) and transgenic mouse models of Parkinson’s disease (alpha synuclein -A53T and tau – rTg4510).
Interestingly, PBT434 also demonstrated neuroprotective properties in animal models of multiple systems atrophy (or MSA). Suggesting that perhaps iron chelation could be a broad neuroprotective approach.
The researchers concluded that this preclinical data demonstrates the efficacy of PBT434 as a clinical candidate for Parkinson’s disease. PBT434 shows a strong toxicology profile and favourable therapeutic activity. Prana is preparing its pre-clinical development package for PBT434 to initiate human clinical trials.
Does Prana have any other drugs in clinical trials?
Yes, they do.
Prana Biotechnology has another product called PBT2.
The Alzheimer’s study was called the IMAGINE Trial, but (there is always a ‘but’) recently PBT2 failed to meet its primary endpoint (significantly reducing levels of beta-amyloid – the perceived bad guy in Alzheimer’s disease) in a phase III trial of mild Alzheimer’s disease. PBT2 was, however, shown to be safe and very well tolerated over the 52 week trial, with no difference in the occurrence of adverse events between the placebo and treated groups.
In addition, there was less atrophy (shrinkage) in the brains of those patients treated with PBT2 when compared to control brains, 2.6% and 4.0%, respectively (based on brain imaging). The company is tracking measures of brain volume and cognition in a 12 month extension study. It could be interesting to continue that follow up long term to evaluate the consequences of long term use of this drug on Alzheimer’s disease – even if the effect is minimal, any drug that can slow the disease down is useful and could be used in conjunction with other neuroprotective medications.
For Huntington’s disease, the company is also using the PBT2 drug and this study has had a bit more success. The study, called Reach2HD, was a six month phase II clinical trial in 109 patients with early to mid-stage Huntington’s disease, across 20 sites in the US and Australia. The company was aiming to assess the safety profile of this drug in this particular condition, as well as determining the motor and behavioural benefits.
In the ReachHD study, PBT2 showed signs of improving some aspects of cognitive function in the study, which potentially represents a major event for a disease for which there is very little in the way of medical treatments.
For a full description of the PBT2 trials, see this wikipedia page on the topic.
Is Prana the only research group working on iron chelators technology for Parkinson’s disease?
There is a large EU-based consortium called FAIR PARK II, which is running a five year trial (2015 – 2020) of the iron chelator deferiprone (also known as Ferriprox). The study is a multi-centre, placebo-controlled, randomised clinical trial involving 338 people with recently diagnosed Parkinson’s disease.
The population will be divided into two group (169 subjects each). They will then be assigned either deferiprone (15 mg/kg twice a day) or a placebo. Each subject will be given 9-months of treatment followed by a 1-month post-treatment monitoring period, in order to assess the disease-modifying effect of deferiprone (versus placebo).
Deferiprone. Source: SGPharma
As far as we are aware, this FAIR PARK II clinical trial is still recruiting participants – please click here to read more about this – thus it will most likely be some time before we hear the results of this study.
Are there natural sources of chelators?
Yes there are. In fact, many natural antioxidants exert some chelating activities.
Prominent among the natural sources of chelators: Green tea has components of plant extracts, such as epigallocatechin gallate (EGCG – which we have previously discussed in regards to Parkinson’s disease, click here to read that post) which possess structures which infer metal chelating properties.
As we have said before people, drink more green tea!
Anyone fancy a cuppa? Source: Expertrain
So what does it all mean?
Summing up: We do not know what causes Parkinson’s disease. Most of our experimental treatments are focused on the biological events that occur in the brain around and after the time of diagnosis. These include an apparent accumulation of iron in affected brain regions.
Research groups are currently experimenting with drugs that reduce the levels of iron in the brain as a potential treatment for Parkinson’s disease. Preclinical data certainly look positive. We will now have to wait and see if those results translate into the human.
Previous clinical trials of metal chelators in neurodegeneration have had mixed success in demonstrating positive benefits. It may well be, however, that this treatment approach should be used in conjunction with other neuroprotective approaches – as a supplement. It will be interesting to see how Prana Biotechnology’s drug PBT434 fares in human clinical trials for Parkinson’s disease.
Stay tuned for more on this.
UPDATE – 3rd May 2017
Today the results of a double-blind, phase II clinical trial of iron chelator deferiprone in Parkinson’s disease were published. The results of the study indicate a mildly positive effect (though not statistically significant) after 6 months of daily treatment.
Title: Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson’s disease
Authors: Martin-Bastida A, Ward RJ, Newbould R, Piccini P, Sharp D, Kabba C, Patel MC, Spino M, Connelly J, Tricta F, Crichton RR & Dexter DT
Journal: Scientific Reports (2017), 7, 1398.
PMID: 28469157 (This article is OPEN ACCESS if you would like to read it)
In this Phase 2 randomised, double-blinded, placebo controlled clinical trial, the researchers recruited 22 people with early stage Parkinson’s disease (disease duration of less than 5 years; 12 males and 10 females; aged 50–75 years). They were randomly assigned to either a placebo group (8 participants), or one of two deferiprone treated groups: 20 mg/kg per day (7 participants) or 30 mg/kg per day (7 participants). The treatment was two daily oral doses (taken morning and evening), and administered for 6 months with neurological examinations, brain imaging and blood sample collections being conducted at 0, 3 and 6 months.
Deferiprone therapy was well tolerated and brain imaging indicated clearance of iron from various parts of the brain in the treatment group compared to the placebo group. Interestingly, the 30 mg/kg deferiprone treated group demonstrated a trend for improvement in motor-UPDRS scores and quality of life (although this was not statistically significance). The researchers concluded that “more extensive clinical trials into the potential benefits of iron chelation in PD”.
Given the size of the groups (7 people) and the length of the treatment period (only 6 months) in this study it is not really a surprise that the researchers did not see a major effect. That said, it is very intriguing that they did see a trend towards motor score benefits in the 30 mg/kg deferiprone group – remembering that this is a double blind study (so even the investigators were blind as to which group the subjects were in).
We will now wait to see what the FAIR PARK II clinical trial finds.
UPDATE: 28th June 2017
Today, the research that Prana biotechnology Ltd was presenting in Vienna earlier this year was published:
Title: The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson’s disease.
Authors: Finkelstein DI, Billings JL, Adlard PA, Ayton S, Sedjahtera A, Masters CL, Wilkins S, Shackleford DM, Charman SA, Bal W, Zawisza IA, Kurowska E, Gundlach AL, Ma S, Bush AI, Hare DJ, Doble PA, Crawford S, Gautier EC, Parsons J, Huggins P, Barnham KJ, Cherny RA.
Journal: Acta Neuropathol Commun. 2017 Jun 28;5(1):53.
PMID: 28659169 (This article is OPEN ACCESS if you would like to read it)
The results suggest that PBT434 is far less potent than deferiprone or deferoxamine at lowering cellular iron levels, but this weakness is compensated by the reduced levels of alpha synuclein accumulation in models of Parkinson’s disease. PBT434 certainly appears to be neuroprotective demonstrating improvements in motor function, neuropathology and biochemical markers of disease state in three different animal models of Parkinson’s disease.
The researchers provide little information as to when the company will be exploring clinical trials for this drug, but in the press release associated with the publication, Dr David Stamler (Prana’s Chief Medical Officer and Senior Vice President, Clinical Development) was quoted saying that they “are eager to begin clinical testing of PBT434”. We’ll keep an eye to the ground for any further news.
FULL DISCLOSURE: Prana Biotechnology Ltd is an Australasian biotechnology company that is publicly listed on the ASX. The information presented here is for educational purposes. Under no circumstances should investment decisions be made based on the information provided here. The SoPD website has no financial or beneficial connection to either company. We have not been approached/contacted by the company to produce this post, nor have we alerted them to its production. We are simply presenting this information here as we thought the science of what the company is doing might be of interest to other readers.
In addition, under absolutely no circumstances should anyone reading this material consider it medical advice. The material provided here is for educational purposes only. Before considering or attempting any change in your treatment regime, PLEASE consult with your doctor or neurologist. Metal chelators are clinically available medications, but it is not without side effects (for more on this, see this website). We urge caution and professional consultation before altering a treatment regime. SoPD can not be held responsible for any actions taken based on the information provided here.
The banner for today’s post was sourced from Prana
A biotech company in Australasia got the green light for the next round in a clinical trial two weeks ago.
Their product: tiny cylinders filled with pig cells.
Their mission: to treat Parkinson’s disease with the regenerative healing properties of naturally occurring cells.
In today’s post we will look at what the company is doing and what will happen next.
We have been contacted by several readers asking for a post on the press release last week regarding the clinical trial being conducted by Living Cell Technologies Limited (LCT).
Two weeks ago LCT received approval to commence the treatment of 6 patients in their third group of subjects in a Phase IIb clinical trial of NTCELL® for Parkinson’s disease, at Auckland City Hospital in New Zealand (Click here for the press release).
The company completed treatment of all six patients in ‘group 2’ of the Phase IIb clinical trial of NTCELL for Parkinson’s disease at the end of 2016. Four patients in the trial had 40 NTCELL microcapsules implanted into the putamen on each side of their brain, and two patients had sham surgery with no NTCELL implanted. They now have approval to repeat this in a third group of subjects.
What do we know about the company?
Founded in 1999, the initial goal of the company was to develop regenerative cell therapies. This goal was to be achieved by transplanting cells from Auckland Island pigs into humans.
The first disease considered for this approach was type 1 diabetes, which is now being pursued by a joint venture company in the US while LCT focuses its attention on Parkinson’s disease.
What are NTCELL microcapsules?
NTCELL is an a tiny capsule, that contains choroid plexus cells (taken from pigs). The capsule is made of a semi permeable membrane that allows all of the good chemicals and nutrients (that the cells are producing) to escape into the surrounding environment. At the same time it doesn’t let the cells escape, nor does it allow negative elements into the capsule. In addition, the bodies immune system can’t get at the foreign cells and remove them due to the membrane surrounding the capsule.
An example of encapsulated cells. Source: LEN
These capsules can be transplanted into the brain of people with neurodegenerative conditions, providing the brains of those individuals with the benefits of supportive chemicals and nutrients.
A brain scan of NTCELL capsules transplanted in the human brain. Source: LCT
Interesting, but what are choroid plexus cells?
Believe it or not, there are some empty spaces inside your brain. Spaces where there are no brain cells (neurons).
These spaces are called the ‘ventricles‘.
In the human brain there are 4 basic divisions of the ventricles as you can see in the image below (the ventricles are the yellow space):
The ventricles and choroid Plexus in the human brain (red coloured regions). Source: PhysRev
The ventricles are filled up with a solution called cerebrospinal fluid. Cerebrospinal fluid is very similar to the liquid portion of blood (or plasma – if you remove the cells from blood, it’s called plasma), except that cerebrospinal fluid is nearly devoid of protein. It is actually made from plasma, but it only contains 0.3% of plasma proteins and about 2/3 of the glucose of blood.
The choroid plexus cells are one of the primary sources of production for the cerebrospinal fluid. That production is actually great – total volume of cerebrospinal fluid in the the average human being turns over almost 4 times per day. Choroid plexus cells can be found in all 4 divisions of the ventricular system (the choroid plexus cells are indicated with red/brown colouring in the image above).
And, um… why pigs?
The choroid plexus cells are sourced from a unique herd of pigs that have been designated pathogen-free. They were originally sourced from the remote sub-Antarctic Auckland Islands, where they have been running around in isolation since 1807.
The not-so-tropical Auckland Islands, south of NZ. Source: Sciblogs
That isolation has made them ‘pathogen free’ – basically there is a reduced likelihood of endogenous infectious agents (eg. porine (pig) retrovirus (or PERVs)) in the cells – which is a good thing when you are planning to stick something in the brain.
What research has been done on NTCELL?
Firstly, regarding the capsules, the company published this report in 2009:
Title: Encapsulated living choroid plexus cells: potential long-term treatments for central nervous system disease and trauma.
Authors: Skinner SJ, Geaney MS, Lin H, Muzina M, Anal AK, Elliott RB, Tan PL.
Journal: J Neural Eng. 2009 Dec;6(6):065001.
In this study, the company looked at the utility of the capsules in rodent brains. One important aspect that they wanted to address was how well the cells survive inside the capsules when placed in the brain. They found that the capsules effectively protected the cells from the host immune system, and they survived for the length of the 6 months study without causing any adverse effects.
The capsules were retrieved from the brains of the rats at the end of the study and the viability of cells was analysed. The researchers found that there was no difference in the production of nutrients from the cells in the capsules at 4 months post implantation, but they did see a decrease of 33% at 6 months. In addition, the number of cells decreased to approximately 40% of the pre-implantation values at 6 months.
We are unsure whether the capsules have been altered for the clinical trial.
The researchers followed this research up in 2013 by publishing this paper:
Title: Recovery of neurological functions in non-human primate model of Parkinson’s disease bytransplantation of encapsulated neonatal porcine choroid plexus cells.
Authors: Luo XM, Lin H, Wang W, Geaney MS, Law L, Wynyard S, Shaikh SB, Waldvogel H, Faull RL, Elliott RB, Skinner SJ, Lee JE, Tan PL.
Journal: J Parkinsons Dis. 2013 Jan 1;3(3):275-91. doi: 10.3233/JPD-130214.
PMID: 24002224 (This article is OPEN ACCESS if you would like to read it)
The researchers wanted to test the capsules in non-human pre-clinical trials. For this purpose they induced Parkinson’s disease in 15 monkeys using the neurotoxin MPTP, waited 10 weeks and then implanted their capsules. Six monkeys were implanted with the NTCELL capsules, 6 were implanted with empty capsules, and 3 received no capsules. The animals were then tested out to 24 weeks post implantation.
The behavioural response was dramatic. Most of the primates with the NTCELL capsules demonstrated positive behavioural benefits by 2 weeks post implantation (becoming statistically significant by 4 weeks), while the controls and empty capsule groups exhibited no behavioural recovery at all across the entire 24 weeks.
In addition to behavioural benefits, the investigators found significantly more dopamine neurons in the brains of the monkeys implanted with the NTCELL capsules when compared to the controls.
These findings were used by the company to justify moving towards clinical trials in humans.
And what do we know about the clinical trial for Parkinson’s disease?
A Phase I/IIa NTCELL clinical trial for the treatment of Parkinson’s disease was completed in June 2015. It was an open label investigation of the safety and clinical effect of NTCELL in 4 people who had been diagnosed with Parkinson’s disease for at least five years.
The trial “met the primary endpoint of safety” and “reversed progression of the disease two years after implant” (as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS)). The NTCELL implantation was well tolerated, with “no adverse events considered to be related to NTCELL”. The results of the trial have not been published, but the press release can be found here.
The results from that trial were used to justify and design a larger Phase IIb trial.
What does Phase IIb mean?
Phase II studies, which are designed to address clinical efficacy and biological activity, can be divided into IIA or IIB, and while there is no stated definition for these labels it is generally agreed that:
- Phase IIA studies are usually pilot studies designed to demonstrate clinical efficacy or biological activity (‘proof of concept’ studies);
- Phase IIB studies look to find the optimum dose at which the drug shows biological activity with minimal side-effects (‘definite dose-finding’ studies) – (Source: Wikipedia).
The goal of this Phase IIb LCT clinical study is to “confirm the most effective dose of NTCELL, define any placebo component of the response and further identify the initial target Parkinson’s disease patient sub group”.
A total of 18 patients under 65 years old are taking part in the trial being conducted at Auckland Hospital and Mercy Ascot Hospital in New Zealand. The company will have to wait 26 weeks until after the last patient is implanted to know whether it has been successful in meeting regulator’s conditions on quality, safety, and efficacy. At the 26 weeks mark, the subjects that received the placebo (empty capsules) will be given the NTCELL capsules.
If the current Phase IIb trial is successful, Living Cell Technologies Limited will be looking to “apply for provisional consent to treat paying patients in New Zealand and launch NTCELL® as the first disease modifying treatment for Parkinson’s disease, in 2017” (Source: Ltcglobal). We will wait to see the results of the current study before passing judgement on whether this situation is likely, though it does seem premature given that by the end of the phase IIb trial only 20 people with Parkinson’s disease will have received the NTCELL treatment. A larger phase III trial may be required. Alternatively, if the results of the current trial are truly spectacular, the company may be able to propose a Phase IV style of trial (also called a ‘post-marketing surveillance’ trial) which would allow them to market their product, but they would be required to maintain a strict program of safety surveillance and ongoing technical analysis of the treatment.
Are other companies trying to do something similar?
Another company, NSgene (in Denmark) has a similar sort of experimental product called NsG0301 which is encapsulated human cells that express the neuroprotective protein, GDNF. NsG0301 is still in preclinical testing however, with the Michael J Fox Foundation helping the company to get the clinical trials started.
Sounds very interesting, but what does it all mean?
So in summary, the biotech company LCT have been given permission to continue with their phase II clinical trial which involves placing tiny capsules which contain cells that release beneficial nutrients into the brains of people with Parkinson’s disease. The company will be blind to which individuals are receiving the capsules with cells in them or empty capsules. They should know later in the year if the trials is successful.
One positive feature of this idea is that immune-suppressant treatments are not required as they are with other forms of transplantation therapies. This means that the patient doesn’t need to take medication which stops the immune system from attacking the foreign cells, because the cells are protected by the capsule membrane. Such medication can leave subjects with reduced immune system responses to illness and thus vulnerable.
Having said that, we are a little concerned that the NTCELL product has not been tested thoroughly enough in Parkinson’s disease for the company to be proposing it for commercial use later this year. For example, the phase I open label results could easily be the result of the placebo effect in practise (as all 4 participants knew they were receiving the capsules. This issue could be resolved with DATscan brain imaging of the first 4 subjects (in the phase I trial).
In addition, we would be interested to know how long the cells inside the capsules keep producing cerebrospinal fluid and other beneficial nutrients once inside the human brain. The rodent study (reviewed above) suggested reductions in production from the cells after just 6 months.
While the NTCELL capsules have been tested in many different models of neurological conditions (see the LCT’s publication page for more on this), the company suffered a set back in 2014 when they retracted one of their key pieces of research which demonstrated the use of NTCELL in a rodent model of Parkinson’s disease (Click here for more on this). The study in question was conducted by LCT between 2007 – 2009, and the results were published in The Journal of Regenerative Medicine in 2011. The study was retracted, however, because “the efficacy conclusions in the publication cannot be confirmed”.
To be fair, the company requested the retraction themselves – which is to their credit – and as a precautionary measure LCT placed a hold on any further patient recruitment in their Phase I/IIa clinical study that was underway at the time. But with this study retracted, the published preclinical research for NTCELL in Parkinson’s disease is largely limited to the primate study reviewed above (we are happy to be corrected on this).
We will be intrigued to see the results of the phase II trial, and (if all goes well) whether the New Zealand regulators will be happy for the product to be made commercially available. Depending on the results, they may request further studies. It will definitely be interesting to follow up long-term the 20 subjects who will have received the NTCELL product by that time.
We watch and wait.
UPDATE FROM 1st MAY 2017:
Today Living Cell Technologies Limited posted the following press release:
Treatment completed for all patients in Parkinson’s trial
Living Cell Technologies Limited has completed treatment of all six patients in the third and final group of patients in the Phase IIb clinical trial of NTCELL® for Parkinson’s disease, at Auckland City Hospital.
Four patients had 120 NTCELL microcapsules implanted into the putamen on each side of their brain, and two patients had sham surgery with no NTCELL implanted. To date there are no safety issues in any of the six patients.
The company is blind to the results until 26 weeks after the completion of group 3 of the trial. The results will then be analysed in accordance with the statistical plan and the conclusions announced. This is anticipated to occur in November 2017. Thereafter the patients who received the placebo will receive the optimal treatment.
The Phase IIb trial aims to confirm the most effective dose of NTCELL, define any placebo component of the response and further identify the initial target Parkinson’s disease patient sub group. Providing the trial is successful, the company will apply for provisional consent in Q4 2017 with a view to treating paying patients in New Zealand in 2018.
“The completion of treatment for the patients in group 3 brings us a step closer to our goals of obtaining provisional consent and launching NTCELL as the first disease modifying treatment for Parkinson’s disease,” says Dr Ken Taylor, CEO of Living Cell Technologies.
FULL DISCLOSURE: Living Cell Technologies Limited (LCT) is an Australasian biotechnology company that is publicly listed on the ASX and NSgene is a privately owned company. Under no circumstances should investment decisions be made based on the information provided here. In addition, SoPD has no financial or beneficial connection to either company. We have not been approached/contacted by either company to produce this post. We are simply presenting this information here following requests from our readers and because we thought the science of what the company is doing might be of interest to other readers. The author of this blog is associated with an individual contracted by LCT, but that individual did not request nor was not made aware of this post before publication.
The banner for today’s post was sourced from the Planner
Today there was a lot of Parkinson’s related activity in the news… well, more than usual at least.
Overnight there was the publication of a blood test for Parkinson’s disease, which looks very sensitive. And this afternoon, Acorda Therapeutics announced positive data for their phase three trial.
In this post, we’ll look at what it all means.
Blood cells. Source: Reference.com
Today we found out about an interesting new study from scientists at Lund University (Sweden), where they are developing a test that can differentiate between different types of Parkinsonisms (See our last post about this) using a simple blood test.
We have previously reported about an Australian research group working on a blood test for Parkinson’s disease, but they had not determined whether their test could differentiate between different kinds of neurodegenerative conditions (such as Alzheimer’s disease). And this is where the Swedish study has gone one step further…
Title: Blood-based NfL: A biomarker for differential diagnosis of parkinsonian disorder
Authors: Hansson O, Janelidze S, Hall S, Magdalinou N, Lees AJ, Andreasson U, Norgren N, Linder J, Forsgren L, Constantinescu R, Zetterberg H, Blennow K, & For the Swedish BioFINDER study
Journal: Neurology, Published online before print February 8, 2017
PMID: N/A (This article is OPEN ACCESS if you would like to read it)
The research group in Lund had previously demonstrated that they could differentiate between people with Parkinson’s disease and other types of Parkinsonism to an accuracy of 93% (Click here to read more on this). That is a pretty impressive success rate – equal to basic clinical diagnostic success rates (click here for more on this).
The difference was demonstrated in the levels of a particular protein, neurofilament light chain (or Nfl). NfL is a scaffolding protein, important to the cytoskeleton of neurons. Thus when cells die and break up, Nfl could be released. This would explain the rise in Nfl following injury to the brain. Other groups (in Germany and Switzerland) have also recently published data suggesting that Nfl could be a good biomarker of disease progression (Click here to read more on this).
There was just one problem: that success rate we were talking about above, it required cerebrospinal fluid. That’s the liquid surrounding your brain and spinal cord, which can only be accessed via a lumbar puncture – a painful and difficult to perform procedure.
Lumbar puncture. Source: Lymphomas Assoc.
Not a popular idea.
This led the Swedish researchers to test a more user friendly approach: blood.
In the current study, the researchers took blood samples from three sets of subjects:
- A Lund set (278 people, including 171 people with Parkinson’s disease (PD), 30 people with Multiple system atrophy (MSA), 19 people with Progressive Supranuclear Palsy (PSP), 5 people with corticobasal syndrome (CBS), and 53 people who were neurologically healthy (controls).
- A London set (117 people, including 20 people with PD, 30 people with MSA, 29 people with PSP, 12 people with CBS, and 26 neurologically healthy controls
- An early disease set (109 people, including 53 people with PD, 28 people with MSA, 22 people with PSP, 6 people with CBS). All of the early disease set had a disease duration less than 3 years.
When the researchers looked at the levels of NfL in blood, they found that they could distinguish between people with PD and people with PSP, MSA, and CBS with an accuracy of 80-90% – again a very impressive number!
One curious aspect of this finding, however, is that the levels of Nfl in people with PD are very similar to controls. So while this protein could be used to differentiate between PD and other Parkinsonisms, it may not be a great diagnostic aid for determining PD verses non-PD/healthy control.
In addition, what could the difference in levels of Nfl between PD and other Parkinsonisms tell us about the diseases themselves? Does PD have less cell death, or a more controlled and orderly cell death (such as apoptosis) than the other Parkinsonisms? These are questions that can be examined in follow up work.
Like we said at the top, it’s been a busy day for Parkinson’s disease: Good news today for Acorda Therapeutics, Inc.
They announced positive Phase 3 clinical trial results for their inhalable L-dopa treatment, called CVT-301, which demonstrated a statistically significant improvement in motor function in people with Parkinson’s disease experiencing OFF periods.
We have previously discussed the technology and the idea behind this approach to treating Parkinson’s disease (Click here for that post).
The ARCUS inhalation technology. Source: ParkinsonsLife
Basically, the inhaler contains capsules of L-dopa, which are designed to break open so that the powder can escape. By sucking on the inhaler (see image below), the open capsule starts spinning, releasing the levodopa into the air and subsequently into the lungs. The lungs allow for quicker access to the blood system and thus, the L-dopa can get to the brain faster. This approach will be particularly useful for people with Parkinson’s disease who have trouble swallowing pills/tablets – a common issue.
The Phase 3, double-blind, placebo-controlled clinical trial evaluated the efficacy and safety of CVT-301 when compared with a placebo in people with Parkinson’s disease who experience motor fluctuations (OFF periods). There were a total of 339 study participants, who were randomised and received either CVT-301 or placebo. Participants self-administered the treatment (up to five times daily) for 12 weeks.
The results were determined by assessment of motor score, as measured by the unified Parkinson’s disease rating scale III (UPDRS III) which measures Parkinson’s motor impairment. The primary endpoint of the study was the amount of change in UPDRS motor score at Week 12 at 30 minutes post-treatment. The change in score for CVT-301 was -9.83 compared to -5.91 for placebo (p=0.009). A negative score indicates an improvement in overall motor ability, suggesting that CVT-301 significantly improved motor score.
The company will next release 12-month data from these studies in the next few months, and then plans to file a New Drug Application (NDA) with the Food and Drug Administration (FDA) in the United States by the middle of the year and file a Marketing Authorization Application (MAA) in Europe by the end of 2017. This timeline will depend on some long-term safety studies – the amount of L-dopa used in these inhalers is very high and the company needs to be sure that this is not having any adverse effects.
All going well we will see the L-dopa inhaler reaching the clinic soon.
The banner for today’s post was sourced from the Huffington Post