Gaucher disease is a genetic disorder caused by the reduced activity of an enzyme, glucocerebrosidase. This enzyme is produced by a region of DNA (or a gene) called GBA – the same GBA gene associated with a particular form of Parkinson’s.
Recently, a Danish company has been testing a new drug that could benefit people with Gaucher disease.
It is only natural to ask the question: Could this drug also benefit GBA-associated Parkinson’s?
In today’s post, we will discuss what Gaucher disease is, how this experimental drug works, and why it would be interesting to test it in Parkinson’s.
Will Shakespeare. Source: Ppolskieradio
The title of this post is a play on words from one of the many famous lines of William Shakespeare’s play, Hamlet.
The original line – delivered by Marcellus (a Danish army sentinel) after the ghost of the dead king appears – reads: If the authorities knew about the problems and chose not to prevent them, then clearly something is rotten in the state of Denmark.
(Act 1, Scene 4)
The title of this post, however, is: Something is interesting in the state of Denmark
This slight change was made because certain Danish authorities know about the problem and they are trying to prevent it. The ‘authorities’ in this situation are some research scientists at a biotech company in Denmark, called Orphazyme.
And the problem is Parkinson’s?
No, the problem is Gaucher disease.
Huh? What is Gaucher disease?
Over the last 12 months, the Silverstein Foundation has quickly established itself as a major focused force in the fight against Parkinson’s.
And when I say ‘focused’, I mean ‘focused’ – the foundation is “actively pursues and invests in cutting edge research with the goal of discovering new therapies for the treatment of Parkinson’s Disease in glucocerebrosidase (GBA) mutation carriers”.
But the output of this effort may well have major benefits for the entire Parkinson’s community.
In today’s post, we will discuss what GBA is, how it functions inside cells, its association with Parkinson’s, and what all of this GBA focused research being funded by the Silverstein Foundation could mean for the Parkinson’s community.
Jonathan Silverstein. Source: Forbes
This is Jonathan Silverstein.
He’s a dude.
He is also a General Partner and a Co-Head of Global Private Equity at OrbiMed – the world’s largest fully dedicated healthcare fund manager. During his time at OrbiMed, the company has invested in healthcare companies that have been involved with over 60 FDA approved products.
In February 2017, he was diagnosed with Parkinson’s disease at just 49 years of age.
Rather than simply accepting this diagnosis, however, Mr Silverstein decided to apply the skills that he has built over a long and successful career in funding biotech technology, and in March 2017, he and his wife, Natalie, set up the Silverstein Foundation.
They raised $6 million from donors and then provided another $10 million of their own money to fund the endeavour, which has funded a dozen research projects and started a new company called Prevail Therapeutics (we’ll come back to this shortly).
The foundation has just one mission: “to actively pursue and invest in cutting edge research with the goal of discovering new therapies for the treatment of Parkinson’s Disease in GBA mutation carriers”
And it seeks to address this by achieving three goals:
- to find a way to halt the progression of Parkinson’s with GBA.
- to identify regenerative approaches to replace the damaged/lost cells
- to find preventative measures
What is ‘GBA’?
Today’s (experimental) post provides something new – an overview of some of the major bits of Parkinson’s-related research that were made available in January 2018.
In January of 2018, the world was rocked by news that New Zealand had become the 11th country in the world to put a rocket into orbit (no really, I’m serious. Not kidding here – Click here to read more). Firmly cementing their place in the rankings of world superpowers. In addition, they became only the second country to have a prime minister get pregnant during their term in office (in this case just 3 months into her term in office – Click here to read more about this).
In major research news, NASA and NOAA announced that 2017 was the hottest year on record globally (without an El Niño), and among the top three hottest years overall (Click here for more on this), and scientists in China reported in the journal Cell that they had created the first monkey clones, named Zhong Zhong and Hua Hua (Click here for that news)
Zhong Zhong the cute little clone. Source: BBC
New research published in the last week provides further experimental support for numerous clinical trials currently being conducted, including one by the biotech company Sanofi Genzyme.
Researchers have demonstrated that tiny proteins which usually reside on the outer wall of cells could be playing an important role in the protein clustering (or aggregation) that characterises Parkinson’s.
In today’s post we will look at this new research and discuss what it could mean for the on going clinical trials for Parkinson’s.
The proverb ‘When the cat is away, the mice will play’ has Latin origins.
Dum felis dormit, mus gaudet et exsi litantro (or ‘When the cat falls asleep, the mouse rejoices and leaps from the hole’)
It was also used in the early fourteenth century by the French: Ou chat na rat regne (‘Where there is no cat, the rat is king’).
And then Will Shakespeare used it in Henry the Fifth(1599), Act I, Scene II:
Westmoreland, speaking with King Henry V, Gloucester, Bedford, Exeter and Warwick
“But there’s a saying very old and true,
‘If that you will France win,
Then with Scotland first begin:’
For once the eagle England being in prey,
To her unguarded nest the weasel Scot
Comes sneaking and so sucks her princely eggs,
Playing the mouse in absence of the cat,
To tear and havoc more than she can eat”
Interesting. But what does any of this have to do with Parkinson’s?
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
Gene therapy involves treating medical conditions at the level of DNA – that is, altering or enhancing the genetic code inside cells to provide therapeutic benefits rather than simply administering drugs. Usually this approach utilises specially engineered viruses to deliver the new DNA to particular cells in the body.
For Parkinson’s, gene therapy techniques have all involved direct injections of these engineered viruses into the brain – a procedure that requires brain surgery. This year, however, we have seen the EXTREMELY rapid development of a non-invasive approach to gene therapy for neurological condition, which could ultimately see viruses being injected in the arm and then travelling up to the brain where they will infect just the desired population of cells.
Last week, however, this approach hit a rather significant obstacle.
In today’s post, we will have a look at this gene therapy technology and review the new research that may slow down efforts to use this approach to help to cure Parkinson’s.
Gene therapy. Source: rdmag
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 begun to see more and more 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.
A good 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 – 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?
In addition to looking at current Parkinson’s disease research on this website, I like to look at where technological advances are taking us with regards to future therapies.
In July of this year, I wrote about a new class of engineered viruses that could potentially allow us to treat conditions like Parkinson’s disease using a non-invasive, gene therapy approach (Click here to read that post). At the time I considered this technology way off at some point in the distant future. Blue sky research. “Let’s wait and see” – sort of thing.
So imagine my surprise when an Italian research group last weekend published a new research report in which they used this futurist technology to correct a mouse model of Parkinson’s disease. Suddenly the distant future is feeling not so ‘distant’.
In today’s post we will review and discuss the results, and look at what happens next.
Technological progress – looking inside the brain. Source: Digitial Trends
I have said several times in the past that the pace of Parkinson’s disease research at the moment is overwhelming.
So much is happening so quickly that it is quite simply difficult to keep up. Not just here on the blog, but also with regards to the ever increasing number of research articles in the “need to read” pile on my desk. It’s mad. It’s crazy. Just as I manage to digest something new from one area of research, two or three other publications pop up in different areas.
But it is the shear speed with which things are moving now in the field of Parkinson’s research that is really mind boggling!
Take for example the case of Squalamine.
In February of this year, researchers published an article outlining how a drug derived from the spiny dogfish could completely suppress the toxic effect of the Parkinson’s associated protein Alpha Synuclein (Click here to read that post).
The humble dogfish. Source: Discovery
And then in May (JUST 3 MONTHS LATER!!!), a biotech company called Enterin Inc. announced that they had just enrolled their first patient in the RASMET study: a Phase 1/2a randomised, controlled, multi-center clinical study evaluating a synthetic version of squalamine (called MSI-1436) in people with Parkinson’s disease. The study will enrol 50 patients over a 9-to-12-month period (Click here for the press release).
Wow! That is fast.
Yeah, I thought so too, but then this last weekend a group in Italy published new research that completely changed my ideas on the meaning of the word ‘fast’. Regular readers will recall that in July I discussed amazing new technology that may one day allow us to inject a virus into a person’s arm and then that virus will make it’s way up to the brain and only infect the cells that we want to have a treatment delivered to. This represents non-invasive (as no surgery is required), gene therapy (correcting a medical condition with the delivery of DNA rather than medication). This new study used the same virus we discussed in July.
This week a group of scientists have published an article which indicates differences between mice and human beings, calling into question the use of these mice in Parkinson’s disease research.
The results could explain way mice do not get Parkinson’s disease, and they may also partly explain why humans do.
In today’s post we will outline the new research, discuss the results, and look at whether Levodopa treatment may (or may not) be a problem.
The humble lab mouse. Source: PBS
Much of our understanding of modern biology is derived from the “lower organisms”.
From yeast to snails (there is a post coming shortly on a snail model of Parkinson’s disease – I kid you not) and from flies to mice, a great deal of what we know about basic biology comes from experimentation on these creatures. So much in fact that many of our current ideas about neurodegenerative diseases result from modelling those conditions in these creatures.
Now say what you like about the ethics and morality of this approach, these organisms have been useful until now. And I say ‘until now’ because an interesting research report was released this week which may call into question much of the knowledge we have from the modelling of Parkinson’s disease is these creatures.
You see, here’s the thing: Flies don’t naturally develop Parkinson’s disease.
Nor do mice. Or snails.
Or yeast for that matter.
So we are forcing a very un-natural state upon the biology of these creatures and then studying the response/effect. Which could be giving us strange results that don’t necessarily apply to human beings. And this may explain our long history of failed clinical trials.
We work with the best tools we have, but it those tools are flawed…
What did the new research report find?
This is the study:
Title: Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease
Authors: Burbulla LF, Song P, Mazzulli JR, Zampese E, Wong YC, Jeon S, Santos DP, Blanz J, Obermaier CD, Strojny C, Savas JN, Kiskinis E, Zhuang X, Krüger R, Surmeier DJ, Krainc D
Journal: Science, 07 Sept 2017 – Early online publication
The researchers who conducted this study began by growing dopamine neurons – a type of cell badly affected by Parkinson’s disease – from induced pluripotent stem (IPS) cells.
What are induced pluripotent stem cells?
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