The road ahead: 2020

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.


BP

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.

# # # # # # # # # # #

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.

Source: Rand

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.

Source: Unitystone

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:

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2019: Year in review

 

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.

 


Source: a-star

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?

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Monthy research review – December 2019

 

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:

  • Basic biology
  • Disease mechanism
  • Clinical research
  • New clinical trials
  • Clinical trial news
  • Other news
  • Review articles/videos

 


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

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The Lords of LRRK

 

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?

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DBS: location, location, location

 

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?

Source: Youtube

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?

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ROPAD + LIPAD = NOT BAD :)

 

 

 

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.

Source: Hansetag-rostock

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?

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The inflammasome field is heating up

 

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.

 


Source: Science

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?

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The Tau of LRRK2

 

Dense spherical clusters of a protein – called Lewy bodies – are one of the classical hallmarks of the Parkinsonian brain. They are a common pathological feature, but curiously they are not present in all cases of Parkinson’s.

For example, some individuals with certain forms of Parkinson’s associated with specific genetic mutations do not exhibit any Lewy bodies. Variations in a region of DNA called LRRK2 will increase one’s risk of developing Parkinson’s, but many of those who go on to develop LRRK2-associated Parkinson’s will have a complete absence of Lewy bodies in their brains. These cases have represented an enigma for the Parkinson’s research community and have been difficult to reconcile.

Recently, however, researchers from the University of Pennsylvania have reported a different kind of protein clustering in these LRRK2-associated cases with “no Lewy bodies”. The accumulating protein is called Tau.

In today’s post, we will look at what Tau is, review what the new research report found, and discuss what this discovery could potentially mean for the future treatment of Parkinson’s.

 


Neuropathologists conducting a gross examination of a brain. Source: NBC

At present, a definitive diagnosis of Parkinson’s can only be made at the postmortem stage with an examination of the brain.

Until that moment, all cases of Parkinson’s are ‘suspected’. When a neuropathologist makes an examination of the brain of a person who passed away with the clinical features of Parkinson’s, there are two characteristic hallmarks that they will be looking for in order to provide a final diagnosis of the condition:

1.  The loss of specific populations of cells in the brain, such as the dopamine producing neurons in a region called the substantia nigra, which lies in an area called the midbrain (at the base of the brain/top of the brain stem). As the name suggests, the substantia nigra region is visible due to the production of a ‘substance dark’ molecule called neuromelanin in the dopamine neurons. And as you can see in the image below, the Parkinsonian brain has less dark pigmented cells in the substantia nigra region of the midbrain.

The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinsonian brain (right). Source:Memorangapp

2.  Dense, circular clusters (or aggregates) of protein within cells, which are called Lewy bodies.

shutterstock_227273575A cartoon of a neuron, with the Lewy body indicated within the cell body. Source: Alzheimer’s news

A Lewy body is referred to as a cellular inclusion, as they are almost always found inside the cell body. They generally measure between 5–25 microns in diameter (5 microns is 0.005 mm) and thus they are tiny. But when compared to the neuron within which they reside they are rather large (neurons usually measures 40-100 microns in diameter).

A photo of a Lewy body inside of a neuron. Source: Neuropathology-web

Do all Parkinson’s brains have Lewy bodies?

Funnily enough, no.

And this is where the wheels fall off the wagon in our understanding (and ‘definitive’ definition) of Parkinson’s.

What do you mean?

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Monthly Research Review – November 2019

 

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 November 2019.

The post is divided into seven parts based on the type of research:

  • Basic biology
  • Disease mechanism
  • Clinical research
  • New clinical trials
  • Clinical trial news
  • Other news
  • Review articles/videos

 


So, what happened during November 2019?

In world news:

November 4th – Researchers reported that the spacecraft Voyager 2 has reached interstellar space, following Voyager 1’s historic passage six years ago.

November 7th – New Zealand wrote into law zero carbon immission the same day as Collins Dictionary announced that ‘Climate strike’ was the 2019 word of the year (Click here and here to read more about this).

November 18th – A new study suggests that Humpback whales in the South Atlantic have recovered from near-extinction. Counts show the population off Brazil has climbed from about 450 in the 1950s to 25,000 today (Click here to read more about this).

November 23rd – Max the dog put his owners car in reverse and…

 

November 27th – Researchers created strains of Escherichia coli bacteria that consume carbon dioxide for energy instead of organic compounds (Click here and here to read more about this).

In the world of Parkinson’s research, a great deal of new research and news was reported:

In November 2019, there were 738 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (7538 for all of 2019 so far). In addition, there was a wave to news reports regarding various other bits of Parkinson’s research activity (clinical trials, etc).

The top 6 pieces of Parkinson’s news

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Making a strong case for GCase

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.


Source: Medium

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?

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