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:
The title of today’s post is written in jest – my job as a researcher scientist is to find a cure for Parkinson’s disease…which will ultimately make my job redundant! But all joking aside, today was a REALLY good day for the Parkinson’s community.
Last night (3rd August) at 23:30, a research report outlining the results of the Exenatide Phase II clinical trial for Parkinson’s disease was published on the Lancet website.
And the results of the study are good:while the motor symptoms of Parkinson’s disease subject taking the placebo drug proceeded to get worse over the study, the Exenatide treated individuals did not.
The study represents an important step forward for Parkinson’s disease research. In today’s post we will discuss what Exenatide is, what the results of the trial actually say, and where things go from here.
Last night, the results of the Phase II clinical trial of Exenatide in Parkinson’s disease were published on the Lancet website. In the study, 62 people with Parkinson’s disease (average time since diagnosis was approximately 6 years) were randomly assigned to one of two groups, Exenatide or placebo (32 and 30 people, respectively). The participants were given their treatment once per week for 48 weeks (in addition to their usual medication) and then followed for another 12-weeks without Exenatide (or placebo) in what is called a ‘washout period’. Neither the participants nor the researchers knew who was receiving which treatment.
At the trial was completed (60 weeks post baseline), the off-medication motor scores (as measured by MDS-UPDRS) had improved by 1·0 points in the Exenatide group and worsened by 2·1 points in the placebo group, providing a statistically significant result (p=0·0318). As you can see in the graph below, placebo group increased their UPDRS motor score over time (indicating a worsening of motor symptoms), while Exenatide group (the blue bar) demonstrated improvements (or a lowering of motor score).
Reduction in motor scores in Exenatide group. Source: Lancet
This is a tremendous result for Prof Thomas Foltynie and his team at University College London Institute of Neurology, and for the Michael J Fox Foundation for Parkinson’s Research who funded the trial. Not only do the results lay down the foundations for a novel range of future treatments for Parkinson’s disease, but they also validate the repurposing of clinically available drug for this condition.
In this post we will review what we know thus far. And to do that, let’s start at the very beginning with the obvious question:
So what is Exenatide?
In October 2015, researchers from Georgetown University announced the results of a small clinical trial that got the Parkinson’s community very excited. The study involved a cancer drug called Nilotinib, and the results were rather spectacular.
What happened next, however, was a bizarre sequence of disagreements over exactly what should happen next and who should be taking the drug forward. This caused delays to subsequent clinical trials and confusion for the entire Parkinson’s community who were so keenly awaiting fresh news about the drug.
Earlier this year, Georgetown University announced their own follow up phase II clinical trial and this week a second phase II clinical trial funded by a group led by the Michael J Fox foundation was initiated.
In todays post we will look at what Nilotinib is, how it apparently works for Parkinson’s disease, what is planned with the new trial, and how it differs from the ongoing Georgetown Phase II trial.
The FDA. Source: Vaporb2b
This week the U.S. Food and Drug Administration (FDA) has given approval for a multi-centre, double-blind, randomised, placebo-controlled Phase IIa clinical trial to be conducted, testing the safety and tolerability of Nilotinib (Tasigna) in Parkinson’s disease.
This is exciting and welcomed news.
What is Nilotinib?
Nilotinib (pronounced ‘nil-ot-in-ib’ and also known by its brand name Tasigna) is a small-molecule tyrosine kinase inhibitor, that has been approved for the treatment of imatinib-resistant chronic myelogenous leukemia (CML).
What does any that mean?
Basically, it is the drug that is used to treat a type of blood cancer (leukemia) when the other drugs have failed. It was approved for treating this cancer by the FDA in 2007.
In this post I review recently published research describing interesting new gene therapy tools.
“Gene therapy” involved using genetics, rather than medication to treat conditions like Parkinson’s disease. By replacing faulty sections of DNA (or genes) or providing supportive genes, doctors hope to better treat certain diseases.
While we have ample knowledge regarding how to correct or insert genes effectively, the problem has always been delivery: getting the new DNA into the right types of cells while avoiding all of the other cells.
Now, researchers at the California Institute of Technology may be on the verge of solving this issue with specially engineered viruses.
Gene therapy. Source: yourgenome
When you get sick, the usual solution is to visit your doctor. They will prescribe a medication for you to take, and then all things going well (fingers crossed/knock on wood) you will start to feel better. It is a rather simple and straight forward process, and it has largely worked well for most of us for quite some time.
As the overall population has started to live longer, however, we have become more and more exposed to chronic conditions which require long-term treatment regimes. The “long-term” aspect of this means that some people are regularly taking medication as part of their daily lives. In many cases, these medications are taken multiple times per day.
An example of this is Levodopa (also known as Sinemet or Madopar) which is the most common treatment for the chronic condition of Parkinson’s disease. When you swallow your Levodopa pill, it is broken down in the gut, absorbed through the wall of the intestines, transported to the brain via our blood system, where it is converted into the chemical dopamine – the chemical that is lost in Parkinson’s disease. This conversion of Levodopa increases the levels of dopamine in your brain, which helps to alleviate the motor issues associated with Parkinson’s disease.
Levodopa. Source: Drugs
This pill form of treating a disease is only a temporary solution though. People with Parkinson’s disease – like other chronic conditions – need to take multiple tablets of Levodopa every day to keep their motor features under control. And long term this approach can result in other complications, such as Levodopa-induced dyskinesias in the case of Parkinson’s.
Yeah, but is there a better approach?
Some researchers believe there is. But we are not quite there yet with the application of that approach. Let me explain:
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.
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
Please excuse our use of UK slang in the title of this post, but a group of Australian researchers have recently discovered something really interesting about Parkinson’s disease.
And being a patriotic kiwi, it takes something REALLY interesting for me to even acknowledge that other South Pacific nation. This new finding, however, could be big.
In today’s post, we will review new research dealing with a protein called SOD1, and discuss what it could mean for the Parkinson’s community.
The number of dark pigmented dopamine cells in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source: Adaptd from Memorangapp
Every Parkinson’s-associated website and every Parkinson’s disease researchers will tell you exactly the same thing when describing the two cardinal features in the brain of a person who died with Parkinson’s disease:
- The loss of certain types of cells (such as the dopamine producing cells of the substantia nigra region of the brain – see the image above)
- The clustering (or aggregation) of a protein called Alpha synuclein in tightly packed, circular deposits, called Lewy bodies (see image below).
A Lewy body inside a cell. Source: Adapted from Neuropathology-web
The clustered alpha synuclein protein, however, is not limited to just the Lewy bodies. In the affected areas of the brain, aggregated alpha synuclein can be seen in the branches of cells – see the image below where alpha synuclein has been stained brown on a section of brain from a person with Parkinson’s disease.
Examples of Lewy neurites (indicated by arrows). Source: Wikimedia
Now, one of the problems with our understanding of Parkinson’s disease is disparity between the widespread presence of clustered alpha synuclein and very selective pattern of cell loss. Alpha synuclein aggregation can be seen distributed widely around the affected areas of the brain, but the cell loss will be limited to specific populations of cells.
If the disease is killing a particular population of cells, why is alpha synuclein clustering so wide spread?
So why is there a difference?
We don’t know.
It could be that the cells that die have a lower threshold for alpha synuclein toxicity (we discussed this is a previous post – click here?).
But this question regarding the difference between these two features has left many researchers wondering if there may be some other protein or agent that is actually killing off the cells and then disappearing quickly, leaving poor old alpha synuclein looking rather guilty.
Poor little Mr “A Synuclein” got the blame, but his older brother actually did it! Source: Youtube
And this is a very serious discussion point.
This year of 2017 represents the 200th anniversary of James Parkinson’s first description of Parkinson’s disease, but it also represents the 20th anniversary since the association between alpha synuclein and PD was first established. We have produced almost 7,000 research reports on the topic of alpha synuclein and PD during that time, and we currently have ongoing clinical trials targetting alpha synuclein.
But what if our basic premise – that alpha synuclein is the bad guy – is actually wrong?
Is there any evidence to suggest this?
We are just speculating here, but yes there is.
For example, in a study of 904 brains, alpha synuclein deposits were observed in 11.3% of the brains (or 106 cases), but of those cases only 32 had been diagnosed with a neurodegenerative disorder (Click here to read more on this). The remaining 74 cases had demonstrated none of the clinical features of Parkinson’s disease.
So what else could be causing the cell death?
Well, this week some scientists from sunny Sydney (Australia) reported a protein that could fit the bill.
Sydney. Source: Vagabond
The interesting part of their finding is that the protein is also associated with another neurodegenerative condition: Amyotrophic lateral sclerosis.
Remind me again, what is Amyotrophic lateral sclerosis?
Parkinson’s disease and Amyotrophic lateral sclerosis (ALS) are the second and third most common adult-onset neurodegenerative conditions (respectively) after Alzheimer’s disease. We recently discussed ALS in a previous post (Click here to read that post).
ALS, also known as Lou Gehrig’s disease and motor neuron disease, is a neurodegenerative condition in which the neurons that control voluntary muscle movement die. The condition affects 2 people in every 100,000 each year, and those individuals have an average survival time of two to four years.
You may have heard of ALS due to it’s association with the internet ‘Ice bucket challenge‘ craze that went viral in 2014-15.
The Ice bucket challenge. Source: Forbes
What is the protein associated with ALS?
In 1993, scientists discovered that mutations in the gene called SOD1 were associated with familial forms of ALS (Click here to read more about this). We now know that mutations in the SOD1 gene are associated with around 20% of familial cases of ALS and 5% of sporadic ALS.
The SOD1 gene produces an enzyme called Cu-Zn superoxide dismutase.
This enzyme is a very powerful antioxidant that protects the body from damage caused by toxic free radical generated in the mitochondria.
SOD1 protein structure. Source: Wikipedia
One important note here regarding ALS: the genetic mutations in the SOD1 gene do not cause ALS by affecting SOD1’s antioxidant properties (Click here to read more about this). Rather, researchers believe that the cell death seen in SOD1-associated forms of ALS is the consequences of some kind of toxic effect caused by the mutant protein.
So what did the Aussie researchers find about SOD1 in Parkinson’s disease?
This week, the Aussie researchers published this research report:
Title: Amyotrophic lateral sclerosis-like superoxide dismutase 1 proteinopathy is associated withneuronal loss in Parkinson’s disease brain.
Authors: Trist BG, Davies KM, Cottam V, Genoud S, Ortega R, Roudeau S, Carmona A, De Silva K, Wasinger V, Lewis SJG, Sachdev P, Smith B, Troakes C, Vance C, Shaw C, Al-Sarraj S, Ball HJ, Halliday GM, Hare DJ, Double KL.
Journal: Acta Neuropathol. 2017 May 19. doi: 10.1007/s00401-017-1726-6.
Given that oxidative stress is a major feature of Parkinson’s disease, the Aussie researchers wanted to investigate the role of the anti-oxidant enzyme, SOD1 in this condition. And what they found surprised them.
Heck, it surprised us!
Two areas affected by Parkinson’s disease – the substantia nigra (where the dopamine neurons reside; SNc in the image below) and the locus coeruleus (an area in the brain stem that is involved with physiological responses to stress; LC in the image below) – exhibited little or no SOD1 protein in the control brains.
But in the Parkinsonian brains, there was a great deal of SOD1 protein (see image below).
SO1 staining in PD brain and Control brains. Source: Springer
In the image above, you can see yellowish-brown stained patches in both the PD and control images. This a chemical called neuromelanin and it can be used to identify the dopamine-producing cells in the SNc and LC. The grey staining in the PD images (top) are cells that contain SOD1. Note the lack of SOD1 (grey staining) in the control images (bottom).
Approximately 90% of Lewy bodies in the Parkinson’s affected brains contained SOD1 protein. The investigators did report that the levels of SOD1 protein varied between Lewy bodies. But the clustered (or ‘aggregated’) SOD1 protein was not just present with alpha synuclein, often it was found by itself in the degenerating regions.
The researchers occasional saw SOD1 aggregation in regions of age-matched control brains, and they concluded that a very low level of SOD1 must be inherent to the normal ageing process.
But the density of SOD1 clustering was (on average) 8x higher in the SNc and 4x higher in the LC in the Parkinsonian brain compared to age-matched controls. In addition, the SOD1 clustering was significantly greater in these regions than all of the non-degenerating regions of the same Parkinson’s disease brains.
The investigators concluded that these data suggest an association between SOD1 aggregation and neuronal loss in Parkinson’s disease. Importantly, the presence of SOD1 aggregations “closely reflected the regional pattern of neuronal loss”.
They also demonstrated that the SOD1 protein in the Parkinsonian brain was not folded correctly, a similar characteristic to alpha synuclein. A protein must fold properly to be able to do it’s assigned jobs. By not folding into the correct configuration, the SOD1 protein could not do it’s various functions – and the investigators observed a 66% reduction in SOD1 specific activity in the SNc of the Parkinson’s disease brains.
Interestingly, when the researchers looked at the SNc and LC of brains from people with ALS, they identified SOD1 aggregates matching the SOD1 clusters they had seen in these regions of the Parkinson’s disease brain.
Is this the first time SOD1 has been associated with Parkinson’s disease?
No, but it is the first major analysis of postmortem Parkinsonian brains. SOD1 protein in Lewy bodies has been reported before:
Title: Cu/Zn superoxide dismutase-like immunoreactivity is present in Lewy bodies from Parkinson disease: a light and electron microscopic immunocytochemical study
Authors: Nishiyama K, Murayama S, Shimizu J, Ohya Y, Kwak S, Asayama K, Kanazawa I.
Journal: Acta Neuropathol. 1995;89(6):471-4.
The investigators behind this study reported SOD1 protein was present in Lewy bodies, in the substantia nigra and locus coeruleus of brains from five people with Parkinson’s disease. Interestingly, they showed that SOD1 is present in the periphery of the Lewy body, similar to alpha synuclein. Both of these protein are present on the outside of the Lewy body, as opposed to another Parkinson’s associated protein, Ubiquitin, which is mainly present in the centre (or the core) of Lewy bodies (see image below).
A more recent study also demonstrated SOD1 protein in the Parkinsonian brain, including direct interaction between SOD1 and alpha synuclein:
Title: α-synuclein interacts with SOD1 and promotes its oligomerization
Authors: Helferich AM, Ruf WP, Grozdanov V, Freischmidt A, Feiler MS, Zondler L, Ludolph AC, McLean PJ, Weishaupt JH, Danzer KM.
Journal: Mol Neurodegener. 2015 Dec 8;10:66.
PMID: 26643113 (This article is OPEN ACCESS if you would like to read it)
These researchers found that alpha synuclein and SOD1 interact directly, and they noted that Parkinson’s disease related mutations in alpha synuclein (A30P, A53T) and ALS associated mutation in SOD1 (G85R, G93A) modify the binding of the two proteins to each other. They also reported that alpha synuclein accelerates SOD1 aggregation in cell culture. This same group of researchers published another research report last year in which they noted that aggregated alpha synuclein increases SOD1 clustering in a mouse model of ALS (Click here for more on this).
Are there any genetic mutations in the SOD1 gene that are associated with Parkinson’s disease?
Two studies have addressed this question:
Title: Sequence of the superoxide dismutase 1 (SOD 1) gene in familial Parkinson’s disease.
Authors: Bandmann O, Davis MB, Marsden CD, Harding AE.
Journal: J Neurol Neurosurg Psychiatry. 1995 Jul;59(1):90-1.
PMID: 7608718 (This article is OPEN ACCESS if you would like to read it)
And then in 2001, a second analysis:
Title: Genetic polymorphisms of superoxide dismutase in Parkinson’s disease.
Authors: Farin FM, Hitosis Y, Hallagan SE, Kushleika J, Woods JS, Janssen PS, Smith-Weller T, Franklin GM, Swanson PD, Checkoway H.
Journal: Mov Disord. 2001 Jul;16(4):705-7.
Both studies found no genetic variations in the SOD1 gene that were more frequent in the Parkinson’s affected community than the general population. So, no, there are no SOD1 genetic mutations that are associated with Parkinson’s disease.
Are there any treatments targeting SOD1 that could be tested in Parkinson’s disease?
Great question. Yes there are. And they have already been tested in models of PD:
Title: The hypoxia imaging agent CuII(atsm) is neuroprotective and improves motor and cognitive functions in multiple animal models of Parkinson’s disease.
Authors: Hung LW, Villemagne VL, Cheng L, Sherratt NA, Ayton S, White AR, Crouch PJ, Lim S, Leong SL, Wilkins S, George J, Roberts BR, Pham CL, Liu X, Chiu FC, Shackleford DM, Powell AK, Masters CL, Bush AI, O’Keefe G, Culvenor JG, Cappai R, Cherny RA, Donnelly PS, Hill AF, Finkelstein DI, Barnham KJ.
Title: J Exp Med. 2012 Apr 9;209(4):837-54.
PMID: 22473957 (This article is OPEN ACCESS if you would like to read it)
CuII(atsm) is a drug that is currently under clinical investigation as a brain imaging agent for detecting hypoxia (damage caused by lack of oxygen – Click here to read more about this).
The researchers conducting this study, however, were interested in this compound for other reasons: CuII(atsm) is also a highly effective scavenger of a chemical called ONOO, which can be very toxic. CuII(atsm) not only inhibits this toxicity, but it also blocks the clustering of alpha synuclein. And given that CuII(atsm) is capable of crossing the blood–brain barrier, these investigators wanted to assess the drug for its ability to rescue model of Parkinson’s disease.
And guess what? It did!
And not just in one model of Parkinson’s disease, but FOUR!
The investigators even waited three days after giving the neurotoxins to the mice before giving the CuII(atsm) drug, and it still demonstrated neuroprotection. It also improved the behavioural features of these models of Parkinson’s disease.
Is CuII(atsm) being tested for anything else in Clinical trials?
Yes, there is a clinical trial ongoing for ALS in Australia.
The Phase I study, being run by Collaborative Medicinal Development Pty Limited, is a dose escalating study of Cu(II)ATSM to determine if this drug is safe for use in ALS (Click here for more on this study).
Cu(II)ATSM is an orally administered drug that inhibits the activity of misfolded SOD1 protein. It has been shown to paradoxically increase mutant SOD1 protein in a mouse model of ALS, but it also provides neuroprotection and improves the outcome for these mice (Click here to read more on this).
If this trial is successful, it would be interesting to test this drug on a cohort of people with Parkinson’s disease. Determining which subgroup of the Parkinson’s affected community would most benefit from this treatment is still to be determined. There is some evidence published last year that suggests people with genetic mutations in the Parkinson’s associated gene PARK2 could benefit from the approach (Click here to read more on this). More research, however, is needed in this area.
So what does it all mean?
Right, so summing up, a group of Australian researchers have reported that the ALS associated protein SOD1 is closely associated with the cell death that we observe in the brains of people with Parkinson’s disease.
They suggest that this could highlight a common mechanisms of toxic SOD1 aggregation in both Parkinson’s disease and ALS. Individuals within the Parkinson’s affected community do not appear to have any genetic mutations in the SOD1 gene, which makes this finding is very interesting.
What remains to be determined is whether SOD1 aggregation is a “primary pathological event”, or if it is secondary to some other disease causing agent. We are also waiting to see if a clinical trial targeting SOD1 in ALS is successful. If it is, there may be good reasons for targeting SOD1 as a novel treatment for Parkinson’s disease.
The banner for today’s post was sourced from Pinterest
‘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
This week pre-clinical data was published demonstrating that the Ambroxol is active in the brain.
This is important data given that there is currently a clinical trial being conducted for Ambroxol in Parkinson’s disease.
Today’s post will review the new data and discuss what is happening regarding the clinical trial.
Ambroxol. Source: Skinflint
We have previously discussed the potential use of Ambroxol in the treatment of Parkinson’s disease (Click here to read that post). Today we follow up that post with new data that provides further support for an on-going clinical trial.
Firstly, what is Ambroxol?
Ambroxol is a commonly used treatment for respiratory diseases (the respiratory system being the lungs and related components required for breathing). Ambroxol promotes the clearance of mucus and eases coughing. It also has anti-inflammatory properties, reducing redness in a sore throat. It is the active ingredient of products like Mucosolvan, Mucobrox, and Mucol.
What is the connection between Ambroxol and Parkinson’s disease?
So this is where a gene called GBA comes into the picture.
Genetic mutations in the GBA (full name: Glucosylceramidase Beta) gene are the most common genetic anomaly associated with Parkinson’s disease. People with a mutation in their GBA gene have a higher risk of developing Parkinson’s disease than the general population. And interestingly, people with Parkinson’s disease are approximately five times more likely to carry a GBA mutation than healthy control subjects.
What does GBA do?
The GBA gene provides the instructions for making an enzyme (called glucocerebrosidase) that helps with the digestion and recycling of waste inside cells. The enzyme is located and active inside ‘lysosomes‘.
What are Lysosomes?
Lysosomes are small bags of digestive enzymes that can be found inside cells. They help to break down proteins that have either been brought into the cell or that have served their function and need to be digested and disposed of (or recycled).
How lysosomes work. Source: Prezi
Inside the lysosomes are enzymes like glucocerebrosidase which help to break material down into useful parts. The lysosome will fuse with other small bags (called vacuole) that act as storage vessels of material inside a cell. The enzymes from the lysosome will mix with the material in the vacuole and digest it (or it break down into more manageable components).
Now people with a genetic mutation in their GBA gene will often have an abnormally short, non-functioning version of the glucocerebrosidase enzyme. In those cases the breaking down of waste inside the lysosome becomes inhibited. And if waste can’t be disposed of or recycled properly, things start to go wrong in the cell.
How does Ambroxol correct this?
It was recently shown that Ambroxol triggers exocytosis of lysosomes (Source). Exocytosis is the process by which waste is exported out of the cell.
Exocytosis. Source: Socratic
Thus by encouraging lysosomes to undergo exocytosis and spit their contents out of the cell – digested or not – Ambroxol allows the cell to remove waste effectively and therefore function in a more normal fashion. This mechanism of treatment seemingly bi-passes the faulty glucocerebrosidase digestion enzyme entirely.
Until recently, two important questions, however, have remained unanswered:
- Does Ambroxol enter the brain and have this function there?
- What are the consequences of long term Ambroxol use?
We now have an answer for question no. 1:
Title: Ambroxol effects in glucocerebrosidase and α-synuclein transgenic mice.
Authors: Migdalska-Richards A, Daly L, Bezard E, Schapira AH.
Journal: Ann Neurol. 2016 Nov;80(5):766-775.
PMID: 27859541 (This article is OPEN ACCESS if you would like to read it)
In this study, the researchers treated mice with Ambroxol for 12 days and then measured the level of glucocerebrosidase activity in the brain. They gave Ambroxol to three different groups of mice:
- a group of normal mice,
- a group of mice which had been genetically engineered with a specific mutation in their GBA gene (the heterozygous L444P mutation)
- a group of mice that produced human alpha synuclein (the protein closely associated with Parkinson’s disease).
When they looked at the level of glucocerebrosidase enzyme activity in normal mice, they found an increase of approximately 20% (in mice treated with 4mM Ambroxol). One curious finding was that this dose was the only dose that increase glucocerebrosidase activity (1, 3, and 5mM of Ambroxol had no effect). The investigators noted, however, a reduction in water drinking of mice receiving 5mM in their drinking water (maybe they didn’t like the taste of it!), suggesting that they were not getting as much Ambroxol as the 4mM group.
The 4mM level of of Ambroxol also increased glucocerebrosidase activity in the L444P mutation mice and the alpha-synuclein mice (which interestingly also has reduced levels of glucocerebrosidase activity). One important observation in the alpha synuclein mice was the finding that Ambroxol was able to reduce the levels of alpha synuclein in the cells, indicating better clearance of un-wanted excess of proteins.
These combined results suggested to the investigators that Ambroxol is entering the brain of mice (passing through the protective blood brain barrier) and able to be effective there. In addition, they did not witness any serious adverse effects of ambroxol administration in the mice – an observation made in other studies of Ambroxol in normal mice (Click here to read more about this).
These studies have been followed up by a dosing study in primates which was just published:
Title: Oral ambroxol increases brain glucocerebrosidase activity in a nonhuman primate.
Authors: Migdalska-Richards A, Ko WK, Li Q, Bezard E, Schapira AH.
Journal: Synapse. 2017 Mar 12. doi: 10.1002/syn.21967.
PMID: 28295625 (This article is OPEN ACCESS if you would like to read it)
In this study, the investigators analysed the effect of Ambroxol treatment on glucocerebrosidase activity in three healthy non-human primates. One subject was given an ineffective control solution vehicle, another subject received 22.5 mg/day of Ambroxol and the third subject received 100 mg/day of Ambroxol. They showed that daily administration 100 mg/day of Ambroxol results in increased levels of glucocerebrosidase activity in the brain (approximately 20% increase on average across different areas of the brain). Importantly, the 22.5 mg treatment did not result in any increase.
The investigators wanted to determine if the effect of Ambroxol was specific to glucocerebrosidase, and so they analysed the activity of another lysosome enzyme called beta-hexosaminidase (HEXB). They found that 100 mg/day of Ambroxol also increased HEXB activity (again by approximately 20%), suggesting that Ambroxol may be having an effect on other lysosome enzymes and not just glucocerebrosidase.
The researches concluded that these results provide the first data of the effect of Ambroxol treatment on glucocerebrosidase activity in the brain of non-human primates. In addition, the results indicate that Ambroxol is active and as the researchers wrote “should be further investigated in the context of clinical trials as a potential treatment for Parkinson’s disease”.
And there is a clinical trial currently underway?
Funded by the Cure Parkinson’s Trust and the Van Andel Research Institute (USA), there is currently a phase I clinical trial with 20 people with Parkinson’s disease receiving Ambroxol over 24 months. Importantly, the participants being enrolled in the study have both Parkinson’s disease and a mutation in their GBA gene. The study is being led by Professor Anthony Schapira at the Royal Free Hospital (London).
EDITORS NOTE HERE: Readers may be interested to know that Prof Schapira is also involved with another clinical trial for GBA-associated Parkinson’s disease. The work is being conducted in collaboration with the biotech company Sanofi Genzyme, and involves a phase II trial, called MOVE-PD, which is testing the efficacy, and safety of a drug called GZ/SAR402671 (Click here to read more about this clinical trial). GZ/SAR402671 is a glucosylceramide synthase inhibitor, which will hopefully reduce the production and consequent accumulation of glycosphingolipids in people with a mutation in the GBA gene. This approach is trying to reduce the amount of protein that can not be broken down by the faulty glucocerebrosidase enzyme. The MOVE-PD study will enroll more than 200 patients worldwide (Click here and here to read more on this).
The current Phase 1 trial at the Royal Free Hospital will be primarily testing the safety of Ambroxol in GBA-associated Parkinson’s disease. The researchers will, however, be looking to see if Ambroxol can increase levels of glucocerebrosidase and also assess whether this has any beneficial effects on the Parkinson’s features.
So what does it all mean?
There is a major effort from many of the Parkinson’s disease related charitable groups to clinically test available medications for their ability to slow this condition. Big drug companies are not interested in this ‘re-purposing effort’ as many of these drugs are no longer patent protected and thus providing limited profit opportunities for them. This is one of the unfortunate realities of the pharmaceutical industry business model.
One of the most interesting drugs being tested in this re-purposing effort is the respiratory disease-associated treatment, Ambroxol. Recently new research has been published that indicates Ambroxol is able to enter the brain and have an impact by increasing the level of protein disposal activity.
A clinical trial testing Ambroxol in Parkinson’s disease is underway and we will be watching for the results when they are released (most likely late 2019/early 2020, though preliminary results may be released earlier).
This trial is worth watching.
EDITOR’S NOTE: 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. Amboxol is a commercially available medication, 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 Pharmacybook