Every textbook written about the condition will tell you that the classical pathological characteristic of Parkinson’s is the loss of dopamine neurons in the midbrain region of the brain. It is the distinguishing feature that pathologists look for in order to provide a postmortem diagnosis of the condition.
But what is meant by the words ‘loss of dopamine neurons’? Do the cells actually die? Recently researchers from Korea have published new data exploring this question.
Interestingly, they found evidence of ‘dormant’ dopamine neurons in postmortem sections of brains from people with Parkinson’s – even those with severe forms of the condition.
In today’s post, we will discuss what a dopamine neuron is, what this new research found, and what it could mean for our understanding of Parkinson’s.
2019 represented the centenary year for an important discovery in Parkinson’s research.
In 1919, the Uzbek neuropathologist Konstantin Tretiakoff (1892-1958) reported his findings regarding an examination of 54 human brains.
Konstantin Tretiakoff. Source: Wikipedia
Six of the postmortem brains had belonged to individuals who had suffered from Parkinson’s and three others had been diagnosed with postencephalitic Parkinsonism. In these brains he noticed something rather striking.
What did he find?
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?
Here at the Science of Parkinson’s, we don’t like making predictions – that’s a mug’s game.
We would rather explore interesting ideas based around what we hope to see happen in 2020 – discussing different ways and means by which they could occur – in the hope that some one will pick up the ball and run with it (ideally, they already have the ball and we are as usual naively unaware).
In today’s post, we will outline the SoPD wish list for 2020.
In his excellent biography on Leonado Da Vinci, author Walter Isaacson drops a beautiful hook in the middle of the book to compel the reader on.
As you may be aware, Da Vinci kept lots of journals throughout his life, and he was constantly making drawings and notes. On almost every page, however, he also made list of things to do, and these list suggest an incredibly curious mind.
Isaacson listed a few examples, including:
“Get the master of arithmetic to show you how to square a triangle… Ask Giannino the Bombardier about how the tower of Ferrara is walled… Ask Benedetto Protinari by what means they walk on ice in Flanders… Get a master of hydraulics to tell you how to repair a lock, canal and mill in the Lombard manner…”
But in the middle of the book, Isaacson gives the reader his personal favourite:
“Describe the tongue of the woodpecker”
And then he continues:
“‘Describe the tongue of the woodpecker,’ he instructs himself. Who on earth would decide one day, for no apparent reason, that he wanted to know what the tongue of a woodpecker looks like? How would you even find out? It’s not information Leonardo needed to paint a picture or even to understand the flight of birds”
Wait. What? Woodpeckers have tongues?!?
Here at the SoPD, we are primarily interested in disease modification for Parkinson’s. While there is a great deal of interesting research exploring the causes of the condition, novel symptomatic therapies, and other aspects of Parkinson’s, my focus is generally on the science seeking to slow, stop or reverse the condition.
At the start of each year, it is a useful practise to layout what is planned and what we will be looking for over the next 12 months. Obviously, where 2020 will actually end is unpredictable, but an outline of what is scheduled over the next year will hopefully provide us with a useful resource for better managing expectations.
In this post, I will try to lay out some of what 2020 holds for us with regards to clinical research focused on disease modification for Parkinson’s.
Lord Robert Baden-Powell. Source: Utahscouts
My old scout master once looked around our horse shoe, making eye contact with each of us, before asking the question:
“When did Noah build the ark?”
My fellow scouts and I looked at each other – confused. Did he want an exact date?!?
The scout master waited a moment for one of us to offer up some idiotic attempt at an answer – thankfully no one did – before he solemnly said:
“Before the rain”
It was one of those childhood moments that made little sense at the time, but comes back to haunt you as an adult when you are looking at what the future may hold and trying to plan for it.
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Today’s post is our annual horizon scanning effort, where we lay out what is on the cards for the next 12 months with regards to clinical research focused on disease modification in Parkinson’s.
We will also briefly mention other bits and pieces of preclinical work that we are keeping an eye on for any news of development.
To be clear, this post is NOT intended to be an exercise in the reading of tea leaves – no predictions will be made here. Nor is this a definitive or exhaustive guide of what the next year holds for disease modification research (if you see anything important that I have missed – please contact me). And it should certainly not be assumed that any of the treatments mentioned below are going to be silver bullets or magical elixirs that are going to “cure” the condition.
In the introduction to last year’s outlook, I wrote of the dangers of having expectations (Click here to read that post). I am not going to repeat that intro here, but that the same message applies as we look ahead to what 2020 holds.
In fact, it probably applies even more for 2020, than it did for 2019.
2020 is going to be a busy year for Parkinson’s research, and I am genuinely concerned that posts like this are only going to raise expectations. My hope is that a better understanding of where things currently are and what is scheduled for the next 12 months will help in better managing those expectations. Please understand that there is still a long way to go for all of these experimental therapies.
All of that said, let’s begin:
In this end-of-year post, we review the Parkinson’s research that caught our attention at SoPD HQ in 2019.
Month-by-month we will briefly discuss some of the major pieces of research/announcements that have defined the year and advanced our understanding of Parkinson’s. The list is based on nothing more than the author’s personal opinion – apologies to any researchers who feel left out – and the contents should certainly not be considered definitive or exhaustive.
It was just some of the stuff that made me say “wow” in 2019.
And in the next post, we will conduct our annual horizon scan and consider what 2020 may have in store for us.
2019 was a productive year for the Parkinson’s research community.
Wait a minute. Hold your horses. What is that statement based on?
If we use number of research report published in 2019 as our measure, there was a total of 8094 articles added to the Pubmed website with the tag word “Parkinson’s” attached (compared to 7672 for all of 2018 and 7675 for 2017). That sounds rather productive.
In addition, there were a host of new clinical trials initiatiated, many of which are exploring entirely new experimental therapies. These include:
- UDCA (aka Ursodeoxycholic acid) – A bial acid therapy used for reducing gall stones that may improve mitochondrial function entered Phase II testing for Parkinson’s (Click here to read a SoPD post on the topic).
- PR001 – A gene therapy targetting GBA-associated Parkinson’s (Click here to read a SoPD post about this).
- CNM-Au8 – Gold nanoparticles entered Phase II testing for Parkinson’s (Click here to read an SoPD post about this research).
- Terazosin – This prostatic hyperplasia and hypertension drug was found to enhance Phosphoglycerate kinase 1 (Pgk1) activation & a Phase II trial was immediately initiatiated (Click here to read an SoPD post on this topic).
- Inzomelid – An NLRP3 inhibitor from Inflazome began Phase I testing (Click here to read a SoPD post on this topic).
On top of all of this, numerous novel potenially therapeutic pathways were proposed, such as:
- Farnesyltransferase inhibition (Click here to read a SoPD post on the topic)
- Miro1 degradation (Click here to read an SoPD post on the topic).
- CD22 inhibition (Click here to read a SoPD post on this topic).
- Felodipine – Researchers discovered that this L-type calcium channel blocker & anti-hypertensive drug boosts waste disposal (or autophagy) in mouse brains (Click here to read an SoPD post on the topic).
Plus, there were a number of major Parkinson’s research organisations launched, including the Australian Parkinson’s Mission (Click here to read more about this), Aligning Science Across Parkinson’s (ASAP – click here to read more about this), the Accelerating Medicines Partnership for Parkinson’s disease (or AMP-PD) initiative (Click here to read more about this), and the Chan Zuckerberg Initiative.
Based on all of this, I think it is safe to say that 2019 was a productive year for Parkinson’s research.
Ok, all of that sounds great, but what does that mean for someone living with the condition?
At the end of each month the SoPD writes a post which provides an overview of some of the major pieces of Parkinson’s-related research that were made available during December 2019.
The post is divided into seven parts based on the type of research:
So, what happened during December 2019?
In world news:
December 1-31st – Bush fire continued to rage across Eastern Australia. In New South Wales alone more than 3 million hectares have burned (compared to a total of 900,000 hectares in the Amazon for all of 2019 – Source). Prime Minister Scott Morrison returned home from holiday and signaled “no change” to Australia’s climate policy.
December 10 – Sanna Marin, at the age of 34, became the world’s youngest serving prime minister after being selected to lead Finland’s Social Democratic Party.
December 13th – “Away from the manger” – Sully the camel, Gus the donkey and Rufus the cow were discovered by authorities wandering (towards a Northern star) when they should have been part of the nativity exhibit at the Tanganyika Wildlife Park (Click here to read more about this).
December 30 – Chinese authorities announced that researcher He Jiankui, who claimed to have created the world’s first genetically edited human babies, has been sentenced to three years in prison and fined 3 million yuan (US$430,000) for his genetic research.
In the world of Parkinson’s research, a great deal of new research and news was reported:
In December 2019, there were 792 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (8075 for all of 2019). In addition, there was a wave to news reports regarding various other bits of Parkinson’s research activity (clinical trials, etc).
The top 5 pieces of Parkinson’s news
Here on the SoPD we have discussed the Parkinson’s-associated protein LRRK2 many times. And we look forward to seeing the results of ongoing clinical trials of LRRK2 inhibitors.
But there are significant efforts ongoing to develop therapies that can indirectly target dysfunctional LRRK2 pathways (which may help avoid any potential side effects of direct inhibition)
Recently, researchers in Scotland and California have published research highlighting one such indriect approach to modulating LRRK2.
In today’s post, we will discuss what LRRK2 is, review the new data, and consider the ‘what happens next?’ question.
Prof Dario Alessi. Source: Eureka
Whenever I read a new research report about the activity of the Parkinson’s-associated protein, LRRK2, my first thought is usually “I wonder what Dario thinks of this?”
And I am not alone in this thought.
Prof Dario Alessi – Director of the Medical Research Council Protein Phosphorylation and Ubiquitylation Unit and Professor of Signal Transduction, at the School of Life Sciences, University of Dundee – is widely recognised as one of the leading experts on the research of this particular protein.
University of Dundee. Source: Dundee
His thoughts/opinions are widely sought by many in the field – both academic and industry researchers.
And recently his lab – in collaboration with researchers are Stanford University – published a really interesting new report which we will discuss in today’s post.
But first, the obvious question:
What is LRRK2?
Deep brain stimulation (or DBS) represents a well established treatment option for individuals with Parkinson’s who no longer respond to standard therapies. It involves tiny electrodes being embedded in the brain and they modulate populations of neurons that have become dysfunctional.
The results of the DBS procedure can be “miraculous” for some individuals – reducing tremors and significantly improving quality of life.
In up 20% of cases, however, the procedure may have little or no effect. Placement of the electrodes has been blamed for the lack of DBS response in many of these situations. But very recently researchers have discovered a new method that may aid in the better placement of electrodes.
In today’s post, we will discuss what DBS is, review the new research, and explore the implications of it.
Ray Kroc. Source: Medium
It is said that Ray Kroc – the American fast-food tycoon, who purchased the ‘McDonalds’ company from the McDonald brothers in 1961 for US$2.7 million – once gave a lecture to Harvard MBA students.
At some point during his talk, Mr Kroc asked the students: “What business is McDonalds in?”
You can imagine all the different answers that probably came back: “Food, yeah hamburgers. Right?” “Restaurants!”, “Entertainment“, “Hospitality?”
Mr Kroc simply laughed and said “No”
“Ladies and gentlemen, I’m not in the hamburger business. My business is real estate”
In other words: knowing (and owning) the right locations.
He proceeded to tell the students that big fast food corporations (like McDonalds, Burger King, Subways, Starbucks) spend much of their capital on identifying and buying new locations where they think there will be the opportunity for growth.
I think I’ve got the wrong blog. What on Earth does this have to do with Parkinson’s?
Identifying the right location is very applicable to Parkinson’s when it comes to deep brain stimulation.
What is deep brain stimulation?
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?
When a cell is sick or damaged it will send out signals alerting the immune system that something is wrong. If enough of these molecules are released, they will initate an “immune response” and this process is called inflammation.
There is evidence in neurodegenerative conditions (like Parkinson’s and Alzheimer’s) that the inflammation process is involved, and inhibitors of particular aspects of inflammation are being developed as potential therapies for these conditions.
Of particular interest are drugs targeting the NLRP3 inflammasome.
In today’s post, we will discuss what the NLRP3 inflammasome is, look at new research identifying a novel NLRP3 inflammasome inhibitor, and provide an overview/update of where things are in the clinical testing of NLRP3 inflammasome inhibitors for Parkinson’s.
One of the hottest areas of Parkinson’s research world is ‘inflammation’ (cheesy pun intended).
What is inflammation?
When cells in your body are stressed or sick, they begin to release tiny messenger proteins which inform the rest of your body that something is wrong.
When enough of these messenger proteins are released that the immune system becomes activated, it can cause inflammation.
Inflammation is a critical part of the immune system’s response to trouble. It is the body’s way of communicating to the immune system that something is wrong and activating it so that it can help deal with the situation.
By releasing the messenger proteins (called cytokines), injured/sick cells kick off a process that results in multiple types of immune cells entering the troubled area of the body and undertaking very specific tasks.
The inflammatory process. Source: Trainingcor
The strength of the immune response depends on the volume of the signal arising from those released messenger proteins. And there are processes that can amplify the immune response.
One of those processes is called inflammasomes.
What are inflammasomes?