The great ice hockey player Wayne Gretzky once said “A good hockey player plays where the puck is. A great hockey player plays where the puck is going to be” (the original quote actually came from his father, Walter).
At the start of each year, it is a useful practise to layout what is planned for the next 12 months. This can help us better anticipate where ‘the puck’ will be, and allow us to prepare for things further ahead.
2017 was an incredible year for Parkinson’s research, and there is a lot already in place to suggest that 2018 is going to be just as good (if not better).
In this post, we will lay out what we can expect over the next 12 months with regards to the Parkinson’s-related clinical trials research of new therapies.
Charlie Munger (left) and Warren Buffett. Source: Youtube
Many readers will be familiar with the name Warren Buffett.
The charming, folksy “Oracle of Omaha” is one of the wealthiest men in the world. And he is well known for his witticisms about investing, business and life in general.
Warren Buffett. Source: Quickmeme
He regularly provides great one liners like:
“We look for three things [in good business leaders]: intelligence, energy, and integrity. If they don’t have the latter, then you should hope they don’t have the first two either. If someone doesn’t have integrity, then you want them to be dumb and lazy”
“Work for an organisation of people you admire, because it will turn you on. I always worry about people who say, ‘I’m going to do this for ten years; and if I really don’t like it very much, then I’ll do something else….’ That’s a little like saving up sex for your old age. Not a very good idea”
“Choosing your heroes is very important. Associate well, marry up and hope you find someone who doesn’t mind marrying down. It was a huge help to me”
Mr Buffett is wise and a very likeable chap.
Few people, however, are familiar with his business partner, Charlie Munger. And Charlie is my favourite of the pair.
At the end of each year, it is a useful practise to review the triumphs (and failures) of the past 12 months. It is an exercise of putting everything into perspective.
2017 has been an incredible year for Parkinson’s research.
And while I appreciate that statements like that will not bring much comfort to those living with the condition, it is still important to consider and appreciate what has been achieved over the last 12 months.
In this post, we will try to provide a summary of the Parkinson’s-related research that has taken place in 2017 (Be warned: this is a VERY long post!)
The number of research reports and clinical trial studies per year since 1817
As everyone in the Parkinson’s community is aware, in 2017 we were observing the 200th anniversary of the first description of the condition by James Parkinson (1817). But what a lot of people fail to appreciate is how little research was actually done on the condition during the first 180 years of that period.
The graphs above highlight the number of Parkinson’s-related research reports published (top graph) and the number of clinical study reports published (bottom graph) during each of the last 200 years (according to the online research search engine Pubmed – as determined by searching for the term “Parkinson’s“).
PLEASE NOTE, however, that of the approximately 97,000 “Parkinson’s“-related research reports published during the last 200 years, just under 74,000 of them have been published in the last 20 years.
That means that 3/4 of all the published research on Parkinson’s has been conducted in just the last 2 decades.
And a huge chunk of that (almost 10% – 7321 publications) has been done in 2017 only.
So what happened in 2017? Continue reading
Our apologies to anyone who is squeamish about needles, but this is generally how most people get their seasonal flu vaccination.
Why are we talking about flu vaccines?
Because new research, published last week, suggests everyone should be going out and getting them in the hope of reducing our risk of Parkinson’s disease.
In today’s post we will review the research, exactly what a flu vaccine is, and how it relates to Parkinson’s disease.
Electron micro photograph of Influenza viruses. Source: Neuro-hemin
Long time readers of the SoPD blog will know that I have a particular fascination with theories regarding a viral or microbial role in the development of Parkinson’s disease (the ‘idiopathic’ – or arising spontaneously – variety at least).
Numerous reasons. For example:
- The targeted nature of the condition (why are only selective groups of cells are lost in the brain during the early stages of the condition?)
- The unexplained protein aggregation (eg. Lewy bodies; could they be a cellular defensive mechanism against viruses/microbes – Click here to read more on this idea)
- The asymmetry of the onset (why do tremors start on only one side of the body in most cases?)
And we have previously discussed research here on the website regarding possible associations between Parkinson’s disease and and various types of viruses (including Hepatitis C, Herpes Simplex, and Influenza).
Today we re-visit influenza as new research has been published on this topic.
What is influenza?
Influenza is a single-stranded, RNA virus of the orthomyxovirus family of viruses.
A schematic of the influenza virus. Source: CDC
It is the virus that causes ‘the flu’ – (runny nose, sore throat, coughing, and fatigue) – with the symptom arising two days after exposure and lasting for about a week. In humans, there are three types of influenza viruses, called Type A, Type B, and Type C. Type A are the most virulent in humans. The influenza virus behind both of the outbreaks in the 1918 pandemic was a Type A.
Schematic of Influenza virus. Source: Bcm
As the image above indicates, the influenza virus has a rounded shape, with “HA” (hemagglutinin) and “NA” (neuraminidases) proteins on the outer surface of the virus. The HA protein allows the virus to stick to the outer membrane of a cell. The virus can then infect the host cell and start the process of reproduction – making more copies of itself. The NA protein is required for the virus to exit the host cell and go on to infect other cells. Different influenza viruses have different combinations of hemagglutinin and neuraminidase proteins, hence the numbering. For example, the Type A virus that caused the outbreaks in the 1918 pandemic was called H1N1.
Inside the influenza virus, there are there are eight pieces (segments) of RNA, hence the fact that influenza is an RNA virus. Some viruses have DNA while others have RNA. The 8 segments of RNA provide the information that is required for making new copies of the virus. Each of these segments provides the instructions for making one or more proteins of the virus (eg. segment 4 contains the instructions to make the HA protein).
The 8 segments of RNA in influenza. Source: URMC
The Influenza virus is one of the most changeable viruses we are aware of, which makes it such a tricky beast to deal with. Influenza uses two techniques to change over time. They are called shift and drift.
Shifting is an sudden change in the virus, which produces a completely new combination of the HA and NA proteins. Virus shift can take place when a person or animal is infected with two different subtypes of influenza. When new viral particles are generated inside the cell, there is a mix of both subtypes of virus which gives rise to an all new type of virus.
An example of viral shift. Source: Bcm
Drifting is the process of random genetic mutation. Gradual, continuous, spontaneous changes that occur when the virus makes small “mistakes” during the replication of its RNA. These mistakes can results in a slight difference in the HA or NA proteins, and although those changes are small, they can be significant enough that the human immune system will no longer recognise and attack the virus. This is why you can repeatedly get the flu and why flu vaccines must be administered each year to combat new forms of circulating influenza virus.
What is a flu jab exactly?
Seasonal flu vaccination is a treatment that is given each year to minimise the risk of being infected by an influenza virus.
The ‘seasonal’ part of the label refers to the fact that the flu vaccine changes each year. Most flu vaccines target three strains of the viruses (and are thus called ‘Trivalent flu vaccines’) which are selected each year based on data collected by various health organisations around the world.
The three chosen viruses for a particular year are traditionally injected into and grown in hens’ eggs, then harvested and purified before the viral particles are chemically deactivated. The three dead viruses are then pooled together and packaged as a vaccine. As you can see in the image below, the process of vaccine production is laborious and takes a full year:
The process of vaccine production. Source: Linkedin
By injecting people with the dead viruses from three different strains of the influenza virus, however, the immune system has the chance to build up a defence against those viruses without the risk of the individual becoming infected (the dead viruses in the vaccine can not infect cells).
Flu vaccines cause the immune system to produce antibodies which are used by the immune system to help defend the body against future attacks from viruses. These antibodies generally take about two weeks to develop in the body after vaccination.
As we have said most injected flu vaccines protect against three types of flu virus. Generally each of the three viruses is taken from the following strains:
- Influenza A (H1N1) – the strain of flu that caused the swine flu pandemic in 2009.
- Influenza A (H3N2) – a strain of flu that mainly affects the elderly and people at risk with long term health conditions. In 2016/17 the vaccine contains an A/Hong Kong/4801/2014 H3N2-like virus.
- Influenza B – a strain of flu that particularly affects children. In 2016/17 the vaccine contains B/Brisbane/60/2008-like virus.
How effective are the vaccines?
Well, it really depends on which strains of influenza are going to affect the most people each year, and this can vary greatly. Overall, however, research from the Centers for Disease Control and Prevention (or CDC) suggests that the seasonal flu vaccine reduces the chance of getting sick by approximately 50% (Source). Not bad when you think about it.
Ok, so are there actually any connections between influenza and Parkinson’s disease?
This question is up for debate.
There are certainly some tentative associations between influenza and Parkinson’s disease. Early on, those connections were coincidental, but more recently research is suggesting that there could be a closer relationship.
Between January 1918 and December 1920 there were two outbreaks of an influenza virus during an event that became known as the 1918 flu pandemic. Approximately 500 million people across the globe were infected by the H1N1 influenza virus, and this resulted in 50 to 100 million deaths (basically 3-5% of the world’s population). Given that is occurred during World War 1, censors limited the media coverage of the pandemic in many countries in order to maintain morale. The Spanish media were not censored, however, and this is why the 1918 pandemic is often referred to as the ‘Spanish flu’.
1918 Spanish flu. Source: Chronicle
At the same time that H1N1 was causing havoc, a Romanian born neurologist named Constantin von Economo reported a number of unusual symptoms which were referred to as encephalitis lethargica (EL). This disease left victims in a statue-like condition, speechless and motionless.
Constantin von Economo. Source: Wikipedia
By 1926, EL had spread around the world, with nearly five million people being affected. Many of those who survived never returned to their pre-existing state of health. They were left frozen in an immobile state.
An individual with encephalitis lethargica. Source: Baillement
Historically, it was believed that EL was caused by the influenza virus from the 1918 Spanish influenza pandemic. This was largely due to a temporal association (things happening at approximately the same time) and the finding of influenza antigens in some of the suffers of EL (Click here to read more about this).
And then there were also the observations of Dr Oliver Sacks:
Amazing guy! Dr Oliver Sacks. Source: Pensologosou
During the late 1960s, while employed as a neurologist at Beth Abraham Hospital’s chronic-care facility in New York, Dr Sacks began working with a group of survivors of EL, who had been left immobile by the condition. He treated these individuals with L-dopa (the standard treatment for Parkinson’s disease now, but it was still experimental at the time) and he observed them become miraculously reanimated. The sufferers went from being completely motionless to suddenly active and mobile. Unfortunately the beneficial effects were very short lived.
You may be familiar with Dr Sack’s book about his experience of treating these patients. It is called ‘Awakenings’ and it was turned into a film starring actors Robin Williams and Robert De Niro.
Robin Williams and Robert De Niro in Awakenings. Source: Pinterest
More recent, postmortem analysis of the brains of EL patients found an absence of influenza RNA – click here for more on this), which has led many researchers to simply reject the association between influenza and EL. The evidence supporting this rejection, however, has also been questioned (click here to read more on this), leaving the question of an association between influenza and EL still open for debate.
I think it’s fair to say that we genuinely do not know what caused EL. Whether it was influenza or not is still be undecided.
Ok, so that was the coincidental evidence. Has there been a more direct connection between influenza and Parkinson’s disease?
This is Dr Richard J Smeyne:
He is a research faculty member in the Department of Developmental Neurobiology at St. Jude Children’s Research Hospital (Memphis, Tennessee).
He has had a strong interest in what role viruses like influenza could be playing in the development of Parkinson’s disease, and his research group has published several interesting research reports on this topic, including:
Title: Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration.
Author: Jang H, Boltz D, Sturm-Ramirez K, Shepherd KR, Jiao Y, Webster R, Smeyne RJ.
Journal: Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14063-8.
PMID: 19667183 (This article is OPEN ACCESS if you would like to read it)
Dr Smeyne and his colleagues found in this study that when they injected the highly infectious A/Vietnam/1203/04 (H5N1) influenza virus into mice, the virus progressed from the periphery (outside the brain) into the brain itself, where it induced Parkinson’s disease-like symptoms.
The virus also caused a significant increase in the accumulation of the Parkinson’s disease-associated protein Alpha Synuclein. In addition, they witnessed the loss of dopamine neurons in the midbrain of the mice at 60 days after the infection – that cell loss resembling what is observed in the brains of people with Parkinson’s disease.
Naturally this got the researchers rather excited!
In a follow up study on H5N1, however, these same researchers found that the Parkinson’s disease-like symptoms that they observed were actually only temporary:
Title: Inflammatory effects of highly pathogenic H5N1 influenza virus infection in the CNS of mice.
Authors: Jang H, Boltz D, McClaren J, Pani AK, Smeyne M, Korff A, Webster R, Smeyne RJ.
Journal: Journal for Neuroscience, 2012 Feb 1;32(5):1545-59.
PMID: 22302798 (This article is OPEN ACCESS if you would like to read it)
Dr Smeyne and colleagues repeated the 2009 study and had a closer look at what was happening to the dopamine neurons that were disappearing at 60 days post infection with the virus. When they looked at mice at 90 days post infection, they found that the number of dopamine neurons had returned to their normal number. This pattern was also observed in a region of the brain called the striatum, where the dopamine neurons release their dopamine. The levels of dopamine dropped soon after infection, but rose back to normal by 90 days post infection.
How does that work?
The results suggest that rather than developing new dopamine neurons in some kind of miraculous regenerative process, the dopamine neurons that were infected by the virus simply stopped producing dopamine while they dealt with the viral infection. Once the crisis was over, the dopamine neurons went back to life as normal. And because the researcher use chemicals in the production of dopamine to identify the dopamine neurons, they mistakenly thought that the cells had died when they couldn’t see those chemicals.
One interesting observation from the study was that H5N1 infection in mice induced a long-lasting inflammatory response in brain. The resident helper cells, called microglia, became activated by the infection, but remained active long after the dopamine neurons returned to normal service. The investigators speculated as to whether this activation may be a contributing factor in the development of neurodegenerative disorders.
And this is an interesting idea.
In a follow up study, they investigated this further by looking another influenza viruse that doesn’t actually infect cells in the brain:
Title: Induction of microglia activation after infection with the non-neurotropic A/CA/04/2009 H1N1 influenza virus.
Author: Sadasivan S, Zanin M, O’Brien K, Schultz-Cherry S, Smeyne RJ.
Journal: PLoS One. 2015 Apr 10;10(4):e0124047.
PMID: 25861024 (This article is OPEN ACCESS if you would like to read it)
In this study, a different type of influenza (H1N1) was tested, and while it did not infect the brain, it did cause the microglia cells to flare up and become activated. And again, this activation was sustained for a long period after the infection (at least 90 days).
This is a really interesting finding and relates to the idea of a “double hit” theory of Parkinson’s disease, in which the virus doesn’t necessarily cause Parkinson’s disease but may play a supplemental or distractionary role, grabbing the attention of the immune system while some other toxic agent is also attacking the body. Or perhaps simply weakening the immune system by forcing it to fight on multiple fronts. Alone the two would not cause as much damage, but in combination they could deal a terrible blow.
So what was the flu vaccine research published last week?
Again, from Dr Smeyne’s research group, this report looked whether the combination of an influenza virus infection plus a toxic agent gave a worse outcome than just the toxic agent by itself. An interesting idea for a study, but then the investigators threw in another component: what effect would a influenza vaccine have in such an experiment. And the results are interesting:
Title: Synergistic effects of influenza and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can be eliminated by the use of influenza therapeutics: experimental evidence for the multi-hit hypothesis
Authors: Sadasivan S, Sharp B, Schultz-Cherry S, & Smeyne RJ
Journal: npj Parkinson’s Disease 3, 18
PMID: N/A (This article is OPEN ACCESS if you would like to read it)
What the researchers found was that H1N1-infected mice that were treated with a neurotoxin (called MPTP – a toxin that specifically kills dopamine neurons) exhibit a 20% greater loss of dopamine neurons than mice that were treated with MPTP alone.
And this increase in dopamine neuron loss was completely eliminated by giving the mice the influenza vaccination. The researchers concluded that the results demonstrate that multiple insults (such as a viral infection and a toxin) can enhance the impact, and may even be significant in allowing an individual to cross a particular threshold for developing a disease.
It’s an intriguing idea.
Have epidemiologists (population data researchers) ever investigated a connection between Parkinson’s disease and influenza?
And yes they have:
Title: Parkinson’s disease or Parkinson symptoms following seasonal influenza.
Authors: Toovey S, Jick SS, Meier CR.
Journal: Influenza Other Respir Viruses. 2011 Sep;5(5):328-33.
PMID: 21668692 (This article is OPEN ACCESS if you would like to read it)
In this first study, the researcher used the UK‐based General Practice Research Database to perform a case–control analysis (that means they compare an affected population with an unaffected ‘control’ population. They identified individual cases who had developed an ‘incident diagnosis’ of Parkinson’s disease or Parkinson’s like symptoms between 1994 and March 2007. For each of those case files identified, they matched them with at least four age matched control case files for comparative sake.
Their analysis found that the risk of developing Parkinson’s disease was not associated with previous influenza infections. BUT, they did find that Influenza was associated with Parkinson’s‐like symptoms such as tremor, particularly in the month after an infection. One can’t help but wonder if the dopamine neurons stopped producing dopamine during that period while they dealt with the viral infection.
But of course, I’m only speculating here… and it’s not like there was a second study suggesting that there is actually an association between Parkinson’s disease and influenza.
A year after that first study, a second study was published:
Journal: Association of Parkinson’s disease with infections and occupational exposure to possible vectors.
Authors: Harris MA, Tsui JK, Marion SA, Shen H, Teschke K.
Journal: Movement Disorder. 2012 Aug;27(9):1111-7.
This second study reported that there is actually an association between Parkinson’s disease and influenza.
This investigation was also a case-control study, but it was based in British Columbia, Canada. The researchers recruited 403 individuals detected by their use of antiparkinsonian medications and matched them with 405 control subjects selected from the universal health insurance plan. Severe influenza was associated with Parkinson’s disease at an odds ratio of 2.01 (1 being no difference) and the range of the odds was 1.16-3.48. That’s pretty significant.
Interestingly, the effect is reduced when the reports of infection were restricted to those occurring within 10 years before diagnosis. This observation would suggest that early life infections may have more impact than previously thought.
Curiously, the researchers also found that exposure to certain animals (cats odds ration of 2.06; range 1.09-3.92) and cattle (2.23; range 1.22-4.09) was also associated with developing Parkinson’s disease.
Time to get rid of the pet cow.
Do any other neurodegenerative condition have associations with influenza?
In the limited literature search that we conducted, we only found reports dealing with influenza and Alzheimer’s disease.
Large studies suggest that Alzheimer’s is not associated with influenza (click here to read more on this). Interestingly, the Alzheimer’s associated protein beta amyloid has been shown to inhibit influenza A viruses (Click here to read that report), which may partly explain the lack of any association.
Influenza does have a mild association, however, with depression (Click here to see that report).
So what does it all mean?
A viral theory for Parkinson’s disease has existed since the great epidemic of 1918. Recent evidence points towards several viruses potentially having some involvement in the development of this neurodegenerative condition. And recent evidence suggests that influenza in particular could be particularly influential.
In 1938, Jonas Salk and Thomas Francis developed the first vaccine against flu viruses. It could be interesting for epidemiologists to go back and see if regular flu vaccination usage (if such data exists) reduces the risk of developing Parkinson’s disease.
But until such data is published, however, perhaps it would be wise to go and get a flu vaccine shot.
The banner for today’s post was sourced from the HuntingtonPost
This is one of the first immuno-therapies being tested in Parkinson’s disease, and the results indicate that the treatment was active and well tolerated.
In this post we will review the press release and what it tells us regarding this clinical trial.
Antibodies binding to proteins. Source: AXS
When your body is infected by a foreign agent, it begins to produce some things called antibodies. In most cases, these are Y-shaped proteins that binds to the un-wanted invader and act as a beacon for the immune system. It is a very effective system, allowing us to go about our daily business without getting sick on a regular basis. Antibodies allow us to build up immunity, or resistance of an organism to infection or disease.
Scientist have harnessed the power of this natural process, and they have use it to develop methods of helping our bodies fight off disease.
The first approach is called Acquired Immunity (or adaptive immunity), and it is based on the idea that exposure of the immune system to a pathogen (disease/damage causing agent) creates an ‘immunological memory’ within our immune system, and this leads to an enhanced response to subsequent future encounters with that same pathogen.
Scientists have used the idea of acquired immunity to develop what we call vaccines – which are simply small, neutral fragments of specific pathogen that help the immune system to build up immunity (or resistance) before the body is attacked by the disease-causing pathogen itself.
Vaccination. Source: WebMD
The second approach is called Passive Immunity.
Passive immunisation is simply the sharing of antibodies. And that might sound a bit disturbing, but it is actually a naturally occurring process. For example, a mother’s antibodies are transferred to her baby in the womb via the placenta.
And again, scientists have devised ways of producing passive immunisation artificially. And recently researchers have been using this approach to attack many medical conditions (particularly cancer), in an area of medicine called immunotherapy.
Think of it as simply boosting the immune system by supplementing the supply of antibodies. Scientists can produce high levels of antibodies that specifically target a particular pathogen and then transfer those antibodies to affected people via an intravenous injection.
How is this being used for Parkinson’s disease?
Well, we have previously discussed the idea of a vaccine for Parkinson’s disease (click here to read that post), and we have been closely following the progress of an Austrian company, AffiRis, who are leading the vaccination approach (Click here for that post).
The vaccine approach is targeting the Parkinson’s disease associated protein, Alpha synuclein. It is believed that a bad kind of alpha synuclein is causing the spread of the condition, by being passed from cell to cell. The goal of the vaccine is to capture and remove all of the alpha synuclein being passed between cells and thus (hopefully) halt the progress of – or at least slow down – the disease.
And this week, another company – Prothena – has reported the results of their phase 1 trial for a passive immunity approach to Parkinson’s disease. They have been injecting subjects in the trial with a treatment called PRX002.
(Remember that a phase 1 trial simply tests the safety of a treatment in humans, it is not required to test efficacy of the treatment. Efficacy comes with phases 2 & 3 trials)
What is PRX002?
PRX002 is a monoclonal antibody. The scientists at the biotech company Prothena have artificially produced large amounts of antibodies to alpha synuclein and these have been injected into people with Parkinson’s disease.
Monoclonal antibodies. Source: Astrazeneca
Prothena provide a short video explaining this concept (click here to view the video).
So what were the results of the Prothena study?
The study was conducted in collaboration the pharmaceutical company Roche. It was a double-blind (so both the researchers and subjects did not know what they were receiving until the conclusion of the study), placebo-controlled study involving 80 people with Parkinson’s disease. The subjects were randomly assigned to one of six groups, which received either PRX002 or a placebo. There were six doses of PRX002 tested in the study (0.3, 1, 3, 10, 30 or 60 mg/kg).
The study was conducted over six-month, during which patients received three once-a-month injections of either PRX002 or placebo. The subjects were then followed for an observational period of three months.
According to the press release, no serious treatment-related adverse events were reported in PRX002 treated patients. Mild treatment-related adverse events (greater than anything experienced within the placebo group) were noted in 4 of the 12 subjects in the highest dosage group of PRX002, including constipation and diarrhoea.
Importantly, the investigators reported that thePRX002 antibodies were crossing the blood brain barrier and entering the brain. This resulted in a rapid reduction of alpha-synuclein levels (in some cases by up to 97 percent after a single dose!).
The follow-on Phase 2 clinical study is expected to begin in 2017.
What is the difference between the vaccine and the passive immunity approaches?
Basically, it comes down to levels of control. With a vaccination, once you have injected the vaccine and the immune system is activated, there isn’t much you can do to control the response of the body. And that immune memory is going to last a long time. The passive immunity response, on the other hand, requires regular injections of antibodies which can be stopped if adverse effects are noted.
Plus – and forgive me if I sound a little bit cynical here – drug companies prefer a regular treatment approach (which they can charge for each visit) compared to a one-shot cure. It’s simply a better business model.
What happens next?
In both cases – the vaccine and the passive immunity approaches – phase 2 trials are being set up by the respective companies and we will wait to see have affective these treatments are at slowing down Parkinson’s disease.
If they are affective, expect big headlines in the media and plans for adults everywhere to start being vaccinated. If they fail,…. well, we will have to re-address our understanding of the role of alpha synuclein in Parkinson’s disease.
Interesting times lie ahead.
The banner for todays post was sourced from Prothena
Interest press release from the biotech company AFFiRiS last week (Click here for the press release) regarding their clinical trial of a vaccine for Parkinson’s disease. We have previously outlined the idea behind the trial (Click here for that post) and the team at Michael J Fox foundation also provide a great overview (Click here for that – MJF are partly funding the trial). In today’s post we will briefly review what results AFFiRiS has shared.
Vaccination. Source: WebMD
Vaccination represents an efficient way of boosting the immune system in the targeting of foreign or problematic agents in the body. For a long time it has been believed that the protein Alpha Synuclein is the ‘problematic agent’ involved in the spread of Parkinson’s disease inside the brain. Alpha synuclein is required inside brain cells for various normal functions. In Parkinson’s disease, however, this protein aggregates for some reason and forms circular clusters inside cells called Lewy bodies.
A lewy body (brown with a black arrow) inside a cell. Source: Cure Dementia
It has been hypothesized (and there is a lot of experimental evidence available to support the idea) that released alpha synuclein – freely floating between brain cells – may be one method by which Parkinson’s disease spread through the brain. With this in mind, groups of scientists (like those at AFFiRiS) are attempting to halt the spread of the condition, by training the immune system to target free-floating alpha synuclein. Vaccination is one method by which this is being attempted.
AFFiRiS is a small biotech company in Vienna (Austria) that has an ongoing clinical trial program for a vaccine (called ‘AFFITOPE® PD01A’) against alpha synuclein. The subjects in the study (22 people with Parkinson’s disease) received four vaccinations – each injection given four-weeks apart – and then the subjects were observed for 2-3 years (6 additional subjects were included in the study for comparative sake, but they did not receive the vaccine.
Last week the company issued a press release regarding a phase 1 trial (AFF008), which indicated that PD01A is safe and well tolerated, and causing an immune response (which is a good thing) in 19 of 22 (86%) of vaccinated subjects. In 12 of those 19 (63%) participants with and immune response, the researchers found alpha-synuclein antibodies in the blood, suggesting that the body was reacting to the injected vaccine and producing antibodies against alpha synuclein (for more on what antibodies are, click here).
The scientists also conducted some exploratory efficacy assessments – to determine if they could see if the vaccine was working clinically and slowing down the disease. Eight of the 19 (42%) subjects with an immune response, had no increase of their dopaminergic medication (eg. L-Dopa) over the course of the observational period (average three years per subject). And five of those eight subjects had stable clinical motor scores at the end of the study.
The company also conducted parallel laboratory-based experiments which indicate that AFFITOPE® PD01A-induced antibodies are binding to alpha-synuclein in various models of Parkinson’s disease.
The company will be presenting the results on a poster at the 4th World Parkinson Congress in Portland, Oregon, USA on September 21.
So this is a good result right?
It is easy to get excited by the results announced in the press release, but they must be taken with a grain of salt. This is a Phase I trial which is only designed to test the safety of a new therapeutic agent in humans. From this point of view: Yes, the study produced a good result – the vaccine was well tolerated by the trial subjects.
Drawing any other conclusions, however, is not really possible – the study was not double-blind and the assignment of subjects to the treatment groups was not randomize. In addition, the small sample size makes it very difficult to make any definitive conclusions. It must be noted that of the 22 people with Parkinson’s disease that started the study, only five exhibited stabilized clinical motor scores at the end of the study. It may be too soon to tell if the vaccine is having an effect in most of the people involved in the study. Thus longer observation periods are required – which the company is currently undertaking with their follow-up study, AFF008AA. The results of that study are expected in middle-late 2017.
We shall keep you posted.
The banner for today’s post was sourced from AFFiRiS
There has never been a more exciting time in Parkinson’s disease research. At no point in the past has the progress been made at such a frenetic pace. New week, new discoveries. And it has to be said that none of this would be possible without the advocacy and fundraising efforts of groups such as the Michael J Fox foundation, the Cure PD Trust, and Parkinson’s UK.
In addition to learning a great deal about the basic science of Parkinson’s disease – a better understanding of the biology underlying the disease – we are also making tremendous gains in new areas of treatment. Until now, the basic treatment has been dopamine replacement with L-dopa. But now, like never before, novel therapeutic approaches are being tested in the clinic.
One of these new approaches, however, is based on a very old idea: Vaccination.
Edward Jenner (1749 – 1823). Source: Wikipedia
While Edward Jenner is considered to be the pioneer of the world’s first vaccine (for Smallpox), the idea of vaccination/inoculation actually originated in India in 1000 BC, where it was briefly mentioned in Sact’eya Grantham, an Ayurvedic text. The first really credible mention of inoculation, however, was in China where it was described in the book Yuyi cao (寓意草 or Notes on My Judgment) by Yu Chang, published in 1643.
Vaccination. Source: WebMD
The basic idea of vaccination is to deliberately introduce an individual to a small component of a disease-causing agent so that the body can build up an immune response to the disease prior to being attacked by the full disease. That fragment of the disease-causing agent becomes what is known as an an ‘antigen’ (this comes from a French word, antigène, derived from the Greek anti- or “against”, and the word-forming suffix -gen, “thing that produces or causes”), and it will serve as the target for the immune system. In response to the antigen, the body produces beacons that bind to the antigen for the immune system to look out for – these beacons are called ‘antibodies’, and they tell the immune system that what they have bound to is ‘not of this body – get rid of it’!
Vaccines will sometimes be made of an empty virus – the surface of the virus will be present, but the internal disease-causing mechanisms have been destroyed or removed. Think of it as training the immune system for some big event. In this way, by exposing and thus priming the body against a particular part of s disease-causing agent, if the body is ever attacked by the full agent, the immune system will be ready to deal with it.
So what does this have to do with Parkinson’s disease?
The AFFiRiS drug (called PD01A in the AFF008 trial) is an vaccine that targets the Parkinson’s disease-related protein ‘Alpha-synuclein’. The vaccine causes the body to produce Alpha-synuclein-specific antibodies. These antibodies allow the immune system to then attack and remove this protein from the blood and fluid surrounding the brain. Any loose alpha-synuclein floating around should be removed.
Alpha-synuclein is a very common protein in the brain – it makes up about 1% of the material in neurons. It is also one of the proteins that is present in the ‘Lewy bodies’ that are associated with Parkinson’s disease.
A cartoon of a neuron, with the Lewy body indicated within the cell body. Source: Alzheimer’s news
Lewy bodies are one of the defining characteristic features of the Parkinsonian brain (having said that, it is interesting to note that approx. 30% of the population over the age of 70 will have Lewy bodies but no clinical symptoms/problems). They are densely packed, spherical shaped, clusters of protein inside the cell body. We are not entirely sure if they are causing cells to die, but they should not be there so it is assumed that if we get rid of them, the cells will be healthier.
An actual photo of a Lewy body (brown) within a neuron. Source: Medicalia
Given that Alpha-synuclein is one of the major components of Lewy bodies, it is the first protein to be targeted by a vaccine for Parkinson’s disease. Some researchers believe that the passing of Alpha synuclein from one cell to another may be the mechanism by which the disease spreads. By removing any Alpha-synuclein that floating around outside of cells, companies like Affiris hope that they will be able to slow down or even halt the spread of Parkinson’s disease within the brain.
The results from the first Affiris trial look rather promising.
The phase one trial run by Affiris was very small (just 12 subjects received the vaccine) and lasted only 12 months. The primary endpoint of any phase one trial is ‘safety and tolerability’ – that is to say, the study is a test of whether the drug is ok for humans use and can be well tolerated (e.g. it has no hidden/unknown side effects). Two different doses of the PD01A vaccine were given in the study and both were well tolerated by the participants in the study.
The Affiris researchers, however, were also looking at a second endpoint in their trial: whether the vaccine caused Alpha Synuclein-specific antibodies to be produced. Thankfully, Affiris found measurable levels of alpha-synuclein-specific antibodies in serum samples (a component of blood) and cerebrospinal fluid (the liquid surrounding the brain) collected from their participants, suggesting that the vaccine is doing it’s job and causing the immune system to react to the antigen being introduced.
Obviously a larger study is now required to determine if the vaccine will actually slow or halt Parkinson’s disease, but when the Affiris researchers compared the subjects in their first trial that received the vaccine with a group of control subjects at the end of the 12 months, they claim that they found PD01A subjects ‘functionally stabilised compared to the control group’.
And Affiris is not the only biotech company trialling the vaccine approach for Parkinson’s disease. In March 2015, an Irish company called ‘Prothena‘ announced that their vaccine reduced Alpha synuclein levels in the serum by 96%! And again the vaccine was well tolerated, with few side effects. 40 subjects were used in the Prothena study and the company will continue to follow them. They expect to release follow-up data – with clinical and imaging results – in early to mid 2016.
We will be watching this area of research very closely. Fingers crossed!