The new year has started with some pleasing clinical trial news for the Parkinson’s community: The results of the “Ambroxol in Disease Modification in Parkinson Disease” (AiM-PD study) have been published.
This is a clinically available drug that is used for the treatment of respiratory issues, which researchers are re-purposing for Parkinson’s based on some interesting properties the drug has.
The results of the clinical trial suggest that ambroxol was safe and well tolerated in people with Parkinson’s for the length of the 6 month study. It accessed the brain and increased levels of target proteins while there.
In today’s post, we will discuss what ambroxol is, what research has been conducted on it, and what the results of this study suggest.
The author of this blog is the deputy director of research at The Cure Parkinson’s Trust, and as such he feels that it is necessary to start this post with a very clear declaration – FULL DISCLOSURE: The Cure Parkinson’s Trust (in partnership with the Van Andel Institute) was a funder of the ambroxol clinical trial which is going to be discussed in this post.
Right. That said, let’s try and do a completely unbiased review of the ambroxol trial results 🙂
In one particular SoPD post last year we discussed the Linked Clinical Trials initiative, which is an international program that was set up 8 years ago with the goal of rapidly repurposing clinically available drugs exhibiting disease modifying potential in models of Parkinson’s (Click here to read the previous SoPD post on this topic).
What is meant by repurposing?
Drug repurposing (repositioning, reprofiling or re-tasking) is a strategy of identifying novel uses for clinically approved drugs that fall outside the scope of the original medical indication.
An example of this is “Viagra”.
It was originally developed as an anti-hypertensive medication, but was hugely more successful in the treatment of erectile dysfunction.
The strategy has been adopted and applied by many organisations because it allows for the by-passing of large parts of the drug discovery process, saving time and resources in getting new treatments to the clinic.
By repurposing a clinically approved drug – for which we may know a great deal about already in terms of safety, tolerability and dose range – we can skip large parts of the clinical trial process and jump straight to testing the drug in our population of interest (in this case people with Parkinson’s).
And this is what the Linked Clinical Trials (or LCT) program was set up to do in Parkinson’s.
The first drug that was prioritised by the LCT committee for repurposing was a diabetes drug called exenatide (also known as Bydureon).
It is fair to say this LCT-initiated clinical trial program has provided interesting results thus far (Click here and here to read a SoPD post on this) and the exenatide program is now entering Phase III testing in Parkinson’s (Click here to read more about the Phase III trial).
In late 2014, the LCT committee prioritised another clinically available drug for repurposing to Parkinson’s.
That drug is called ambroxol.
What is ambroxol?
Approximately 10-20% of Parkinson’s cases are associated with a genetic risk factor which raises the chances of developing the condition.
Tremendous efforts are being made to not only better understand the underlying biology of these associations, but also to identify individuals who may be affected and invite them to take part in innovative new clinical trials.
The challenge is significant, however, as some genetic risk factors only affect less than 1% of the Parkinson’s community, meaning that hundreds of individuals must be genetically screened in order to identify 1 or 2 who might be eligible to take part in any subsequent study.
In today’s post, we will look at one such project (called the “Rostock International Parkinson’s Disease” (or ROPAD) study, and how it is helping to facilitate a second effort called the “LRRK2 International Parkinson’s Disease” (or LIPAD) project.
Rostock: Source: Lerbs
With 200,000+ inhabitants, Rostock was the third largest coastal city in Germany (after Kiel and Lübeck). The city lies on the estuary of the River Warnow in the Bay of Mecklenburg.
Each year, during the second weekend in August, Rostock holds one of the largest yachting events in the world: The Hanse Sail. It is a maritime celebration which attracts more than a million visitors and traditional sailing boats from all over the world.
Rostock is also home to a company called Centogene.
What does Centogene do?
In 2006, neurologist Arndt Rolfs wanted to speed up the diagnosis of rare diseases. To do this, he founded Centogene. The company now has more than 300 employees and has built up one of the world’s largest data repository for genetic information on rare hereditary diseases. It sells genetic testing products and helps pharmaceutical firms develop new drugs for rare conditions.
It is also an instrumental part of a new Parkinson’s research project called ROPAD.
What is ROPAD?
Novel therapies are increasing being developed to focus on specific subtypes of Parkinson’s. The hope is that if they work on one type of Parkinson’s, then maybe they will also work on others.
Many of these new experimental treatments are focused on specific genetic subtypes of the condition, which involve having a specific genetic variation that increases one’s risk of developing Parkinson’s.
Increasing amounts of data, however, are accumulating that some of the biological pathways affected by these genetic variations, are also dysfunctional in people with sporadic (or idiopathic) Parkinson’s – where a genetic variation can not explain the abnormality.
In today’s post, we will review some new research that reports reductions in a specific Parkinson’s-associated biological pathway, and discuss what it could mean for future treatment of the Parkinson’s.
I was recently at a conference on Parkinson’s research where a prominent scientist reminded the audience that just because a person with Parkinson’s carries certain genetic risk factor (an error in a region of their DNA that increases their risk of developing Parkinson’s), does not mean that their Parkinson’s is attributable that genetic variation. Indeed, lots of people in the general population carry Parkinson’s associated genetic risk factors, but never go on to develop the condition.
And this is a really important idea for the Parkinson’s community to understand: Most of the genetics of Parkinson’s deals with ‘association’, not with ‘causation’.
But that begs the question ‘if we do not know that these errors in our DNA are causing Parkinson’s, then why should we be trying to develop therapies based on their biology?’
It is a fair question (it is also a very deep and probing question to start a post off with!).
The genetics of Parkinson’s has been extremely instructive in providing us with insights into the potential underlying biology of the condition. We have learnt a great deal about what many of the biological processess thatare associated with these genetic risk factors, and (yes) various experimental therapies have been developed to target them.
These novel treatments are clinically tested in the hope that they will have beneficial effects not just on individuals carrying certain genetic risk factors, but also on the wider Parkinson’s community.
And recently, there has been increasing evidence supporting this possibility. Some of the biological pathways associated with these genetic mutations appear to also be abnormal in people with Parkinson’s who do not carry the genetic variation.
What do you mean?
Not a week goes by without some new peice of research suggesting yet another biological mechanism that could be useful in slowing or stopping Parkinson’s. This week researchers in Chicago reported that pharmacologically inhibiting a specific enzyme – farnesyltransferase – may represent a novel means of boosting waste disposal and helping stressed cells to survive.
A number of farnesyltransferase inhibitors are being developed for cancer, and there is the possibility of repurposing some of them for Parkinson’s.
In today’s post, we will discuss what farnesyltransferase is and does, what the new research report found, and we will consider whether inhibition of this biological pathway is do-able for Parkinson’s.
I am in the midst of preparing the “end of year review” and “road ahead” posts for 2019/2020 (they take a while to pull together). But it is already extremely apparent that we have an incredible amount of preclinical data piling up,…. and a serious bottleneck at the transition to clinical testing.
It is actually rather disturbing.
Previously this was a concern, but going forward – as more and more novel preclinical work continues to pile up – one can foresee that it is going to be a serious problem.
But there is just SOOOO much preclinical data on Parkinson’s coming out at the moment. Every single week, there is a new method/molecular pathway proposed for attacking the condition.
A good example of this frenetic pace of preclinical research is a recent report from researchers in Chicago, who discovered that a farnesyltransferase inhibitor could be beneficial in Parkinson’s.
The recent documents filed with the U.S. Securities and Exchange Commission by the biotech firm Prevail Therapeutics provides interesting insight into the bold plans of this company which was only founded in 2017.
Even more recent news that the U.S. Food and Drug Administration (FDA) has accepted the company’s Investigational New Drug (IND) application for its lead experimental treatment – PR001 – suggests that this company is not wasting any time.
PR001 is a gene therapy approach targeting GBA-associated Parkinson’s.
In today’s post, we will discuss what GBA-associated Parkinson’s is, how Prevail plans to treat this condition, and discuss what we know about PR001.
Caterina Fake. Source: TwiT
The title of this post comes is from a quote by Caterina Fake (co-founder of Flickr and Hunch (now part of Ebay)), but it seemed appropriate.
This post is all about dreaming big (curing Parkinson’s), the struggle to get the research right, and to create a biotech company: Prevail Therapeutics.
What is Prevail Therapeutics?
Prevail is a gene therapy biotech firm that was founded in 2017.
Dr Asa Abeliovich. Source: Prevail
It was set up in a collaborative effort with The Silverstein Foundation for Parkinson’s with GBA (Click here to read a previous SoPD post about this organisation) and OrbiMed (a healthcare-dedicated investment firm).
What does Prevail Therapeutics do?
As the amazing Australian Parkinson’s Mission project prepares to kick off, across the creek in my home land of New Zealand, another very interesting clinical trial programme for Parkinson’s is also getting started. The study is being conductetd by a US biotech firm called resTORbio Inc.
The drug being tested in the study is called RTB101.
It is an orally-administered TORC1 inhibitor, and it represents a new class of drug in the battle against Parkinson’s.
In today’s post, we will look at what TORC1 is, how the drug works, the preclinical research supporting the trial, and what this new clinical trial will involve.
Rapa Nui. Source: Chile.Travel
Today’s post kicks off on an amazing south Pacific island… which is not New Zealand.
In 1965, a rather remarkable story began in one of the most remote inhabited places on Earth – the mysterious island of Rapa Nui (or “Easter Island”).
And when we say ‘remote’, we really do mean remote. Did you know, the nearest inhabited island to Rapa Nui is Pitcairn Island, which is 2,075 kilometres (1,289 mi) away. And Santiago (the capital of Chile) is 2,500 miles away – that’s a four-hour+ flight!!!
Rapa Nui is the very definition of remote. It is as remote as remote gets!
Does Amazon deliver to the town of Hanga Roa? Source: Atlasandboots
Anyways, in 1965 a group of researchers arrived at Rapa Nui with the goal of studying the local inhabitants. They wanted to investigate their heredity, environment, and the common diseases that affected them, before the Chilean government built a new airport which would open the island up to the outside world.
It was during this investigation, that one of the researchers – a University of Montreal microbiologist named Georges Nógrády – noticed something rather odd.
At the time of the study, wild horses on Rapa Nui outnumbered humans (and stone statues).
Wild horses roaming the east coast of Rapa Nui. Source: Farflungtravels
But what was odd about that?
Georges discovered that locals had a very low frequency of tetanus – a bacterial infection of the feet often found in places with horses. He found this low incidence of tetanus particularly strange given that the locals spent most of their time wandering around the island barefoot. So Georges decided to divide the island into 67 regions and he took a soil sample from each for analysis.
In all of the vials collected, Nógrády found tetanus spores in just one vial.
Something in the soil on Rapa Nui was extremely anti-fungal.
In 1969, Georges’ collection of soil samples was given to researchers from the pharmaceutical company Wyeth and they went looking for the source of the anti-fungal activity. After several years of hard work, the scientists found a soil bacteria called Streptomyces hygroscopicus which secreted a compound that was named Rapamycin – after the name of the island – and they published this report in 1975:
Title: Rapamycin (AY-22, 989), a new antibiotic
Authors: Vézina C, Kudelski A, Sehgal SN.
Journal: J Antibiot (Tokyo). 1975 Oct;28(10):721-6.
PMID: 1102508 (This report is OPEN ACCESS if you would like to read it)
It is no understatement to say that this was a major moment in biomedical history. So much so that there is actually a plaque on the island commemorating the discovery of rapamycin:
Why was the discovery of ‘anti-fungal’ rapamycin so important?!?
This week the ‘Michael J. Fox Foundation for Parkinson’s Research’ and ‘The Silverstein Foundation for Parkinson’s with GBA’ announced that they are collaboratively awarding nearly US$3 million in research grants to fund studies investigating an enzyme called beta glucocerebrosidase (or GCase).
Why is this enzyme important to Parkinson’s?
In today’s post, we will discuss what GCase does, how it is associated with Parkinson’s, and review what some of these projects will be exploring.
This is Jonathan Silverstein.
He is a General Partner 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 – at just 49 years of age – Jonathan was diagnosed with Parkinson’s.
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 for Parkinson’s with GBA.
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
This week, the Silverstein foundation and the Michael J. Fox Foundation for Parkinson’s Research made a big anoouncement.
The two organisations announced nearly US$3 million in grants to fund studies investigating an enzyme called glucocerebrosidase beta acid (or GCase).
And what exactly is glucocerebrosidase?
An important aspect of developing better remedies for Parkinson’s involves determining when and where the condition starts in the brain. What is the underlying mechanism that kicks things off and can it be therapeutically targetted?
Recently, researchers from Japan have suggested that a protein called Myristoylated alanine-rich C-kinase substrate (or simply MARCKS) may be a potentially important player in the very early stages of Parkinson’s (and other neurodegenerative conditions).
Specifically, they have found that MARCKS is present before many of the other pathological hallmarks of Parkinson’s (such as Lewy bodies) even appear. But what does this mean? And what can we do with this information?
In today’s post, we will look at what MARCKS is, what new research suggests, and how the research community are attempting to target this protein.
Where does it all begin? Source: Cafi
One of the most interesting people I met during my time doing Parkinson’s assessment clinics was an ex-fire forensic investigator.
We would generally start each PD assessment session with a “brief history” of life and employment – it is a nice ice breaker to the appointment, helped to relax the individual by focusing on a familiar topic, and it could provide an indication of potential issues to consider in the context of Parkinson’s – such as job related stress or exposure to other potential risk factors (eg. pesticides, etc).
But so fascinated was I with the past emplyoment of the ex-fire forensic investigator gentleman that the “brief history” was anything but brief.
We had a long conversation.
One aspect of fire forensics that particularly fascinated me was the way he could walk into a recently burned down property, and he could “read the story backwards” to identify the root cause of the fire.
He could start anywhere on a burnt out property and find his way back to the source (and also determine if the fire was accidental or deliberate).
Where did it all start? Source: Morestina
I marvelled at this idea.
And I can remember wondering “why can’t we do that with Parkinson’s?”
Well, recently some Japanese researchers have had a crack at “reading the story backwards” and they found something rather interesting.
What did they find?
There is a great deal of interest in genetic risk factors in Parkinson’s at the moment. A number of companies are providing direct-to-consumer services which provide individuals with some information about their family history and whether they have any of the more common genetic variations that are associated with medical conditions, like Parkinson’s.
Recently a new genetic data company has started – called Nebula Genomics – and they are offering a slightly different kind of service.
While many of the direct-to-consumer genetic companies have a business model that involves selling on genetic information to third parties, Nebula is offering a more patient-empowering option.
In today’s post, we will discuss the genetics of Parkinson’s, what Nebula Genomics is offering, and how this new service could be useful for the Parkinson’s community.
Prof George Church. Source: Biospace
Professor George Church is a person most readers will have never heard of.
He is the Robert Winthrop Professor of Genetics at Harvard Medical School and Professor of Health Sciences and Technology at Harvard and MIT, and was a founding member of the Wyss Institute for Biologically Inspired Engineering at Harvard.
He has co-author of over 500 academic papers, 143 patents and co-founded 22 biotech companies. In addition, he has participated in technology development, advising most of the major Genetic Sequencing companies, and he has been at the forefront of genetic research since the 1980s when he was involved with setting up the Human Genome Project.
His impact in the world of genetics has been tremendous.
But Prof Church is also something of a maverick. A left-field thinker. A disrupter.
He is a great supporter of open access genome sequencing and shareable human medical data. He is also keen to bring back extinct species, such as the Woolly Mammoth (Click here for more on this idea).
The return of the woolly mammoth. Source: Phys
Most recently, however, his name has been associated with a new company called Nebula Genomics.
Recently researchers have provided very interesting evidence that a form of vitamin B3, called Nicotinamide Riboside, may have beneficial effects for Parkinson’s.
Their data suggests that nicotinamide riboside was able to rescue problems in mitochondria – the power stations of cells – in both fly and human cell-based models of Parkinson’s.
And the results also suggest that this treatment could prevent the neurodegeneration of dopamine producing neurons.
In today’s post, we will discuss what nicotinamide riboside is, what is does in the body, how it may be having its beneficial effect, and we will consider the pros and cons of taking it as a supplement.
My pile of research reports to read. Source: Reddit
We have a serious problem in biomedical research at the moment.
Serious for ‘planet research’ that is (Good for ‘planet patient’! – click here to understand this sentence).
The problem is very simple: there is too much research going on, and there is now too much information to be absorbed.
There has been an incredible increase in the number of research reports for ‘Parkinson’s’:
For Parkinson’s research alone, every day there is about 20 new research reports (approximately 120 per week). It used to be the case that there was one big research report per year. Then progress got to the crazy point of one big finding per month. And now things are ‘completely kray kray’ (as my 5 year old likes to say), with one new major finding every week!
On top of this, everyday there are new methodology reports, new breakthroughs in other fields that could relate to what is happening in PD, new clinical trial results, etc… The image below perfectly represents how many researchers are currently feeling with regards to the information flow:
How I feel most days. Source: Lean
Don’t get me wrong.
These are very exciting times, big steps are being made in our understanding of conditions like Parkinson’s. It’s just that it is really hard keeping up with the amazing flow of new data.
And this is certainly apparent here on the SoPD website. Occasionally, a few days after I publish something on a particular topic on the SoPD website, a fascinating new research report on that same topic will be published. When I get a chance to read it, I will sometimes add an addendum to the bottom of a post highlighting the new research.
Every now and then, however, the new research deserves a post all of its own.
Which is the case today.
A week after I published the recent Vitamin B3/Niacin post, a new study was published that dealt with a different form of Vitamin B3, called Nicotinamide Riboside. And the results of that study were really interesting.
Wait a minute. Vitamin B3 comes in different forms?