The biotech company Acorda Therapeutics Inc. yesterday announced that it was halting new recruitment for the phase III program of its drug Tozadenant (an oral adenosine A2a receptor antagonist).
In addition, participants currently enrolled in the trial will now have their blood monitoring conducted on a weekly basis.
The initial report looks really bad (tragically five people have died), but does this tragic news mean that the drug should be disregarded?
In todays post, we will look at what adenosine A2a receptor antagonists are, how they may help with Parkinson’s, and discuss what has happened with this particular trial.
Dr Ron Cohen, CEO of Acorda. Source: EndpointNews
Founded in 1995, Acorda Therapeutics Ltd is a biotechnology company that is focused on developing therapies that restore function and improve the lives of people with neurological disorders, particularly Parkinson’s disease.
Earlier this year, they had positive results in their phase III clinical trial of Inbrija (formerly known as CVT-301 – Click here to read a previous post about this). They have subsequently filed a New Drug Application with the US Food and Drug Administration (FDA) to make this inhalable form of L-dopa available in the clinic, but the application has been delayed due to manufacturing concerns from the FDA (Click here to read more about this). These issues should be solvable – the company and the FDA are working together on these matters – and the product will hopefully be available in the new year.
So what was the news yesterday?
Acorda Therapeutics has another experimental product going through the clinical trial process for Parkinson’s disease.
It’s called Tozadenant.
Tozadenant is an oral adenosine A2a receptor antagonist (and yes, we’ll discuss what all that means in a moment).
Yesterday Acorda Therapeutics Inc announced that they have halted new recruitment for their phase III clinical program. In addition the company is increasing the frequency of blood cell count monitoring (from monthly to weekly) for participants already enrolled in the company’s Phase 3 program of Tozadenant for Parkinson’s disease.
The Company took this action due to reports of cases of agranulocytosis.
Recently a Parkinson’s-associated research report was published that was the first of many to come.
It involves the use of a genetic screening experiment that incorporates new technology called ‘CRISPR’.
There is an absolute tidal wave of CRISPR-related Parkinson’s disease research coming down the pipe towards us, and it is important that the Parkinson’s community understands how this powerful technology works.
In today’s post we will look at what the CRISPR technology is, how it works, what the new research report actually reported, and discuss how this technology can be used to tackle a condition like Parkinson’s.
Me and my mother (and yes, the image is to scale). Source: Openclipart
My mother: Simon, what is all this new ‘crispy’ research for Parkinson’s I heard about on the news?
Me: Huh? (I was not really paying attention to the question. Terrible to ignore one’s mother I know, but what can I say – I am the black sheep of the family)
My mother: Yes, something about ‘crispy’ and Parkinson’s.
Me: Oh! You mean CRISPR. Yeah, it’s really cool stuff.
My mother: Ok, well, can you explain it all to me please, this ‘Crisper’ stuff?
CRISPR.101 (or CRISPR for beginners)
In almost every cell of your body, there is a nucleus.
It is the command centre for the cell – issuing orders and receiving information concerning everything going on inside and around the cell. The nucleus is also a storage bank for the genetic blueprint that provides most of the instructions for making a physical copy of you. Those grand plans are kept bundled up in 23 pairs of chromosomes, which are densely coiled strings of a molecule called Deoxyribonucleic acid (or DNA).
DNA’s place inside the cell. Source: Kids.Britannica
This week a biotech company called Voyager Therapeutics announced the results of their ongoing phase Ib clinical trial. The trial is investigating a gene therapy approach for people with severe Parkinson’s disease.
Gene therapy is a technique that involves inserting new DNA into a cell using a virus. The DNA can help the cell to produce beneficial proteins that go on help to alleviate the motor features of Parkinson’s disease.
In today’s post we will discuss gene therapy, review the new results and consider what they mean for the Parkinson’s community.
On 25th August 2012, the Voyager 1 space craft became the first human-made object to exit our solar system.
After 35 years and 11 billion miles of travel, this explorer has finally left the heliosphere (which encompasses our solar system) and it has crossed into the a region of space called the heliosheath – the boundary area that separates our solar system from interstellar space. Next stop on the journey of Voyager 1 will be the Oort cloud, which it will reach in approximately 300 years and it will take the tiny craft about 30,000 years to pass through it.
Where is Voyager 1? Source: Tampabay
Where is Voyager actually going? Well, eventually it will pass within 1 light year of a star called AC +79 3888 (also known as Gliese 445), which lies 17.6 light-years from Earth. It will achieve this goal on a Tuesday afternoon in 40,000 years time.
Gliese 445 (circled). Source: Wikipedia
Remarkably, the Gliese 445 star itself is actually coming towards us. Rather rapidly as well. It is approaching with a current velocity of 119 km/sec – nearly 7 times as fast as Voyager 1 is travelling towards it (the current speed of the craft is 38,000 mph (61,000 km/h).
Interesting, but what does any of that have to do with Parkinson’s disease?
Well closer to home, another ‘Voyager’ is also ‘going boldly where no man has gone before’ (sort of).
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.
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