The basket case

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One of the more interesting pieces of clinical trial news in 2020 was the publication of the results of a “basket study” for neurological conditions. This was a trial that involved a drug being tested on a selection of neurodegenerative conditions, rather than just one condition.

Between December 2013 to May 2017, researchers recruited a total of 29 individuals with Alzheimer’s, 14 with progressive supranuclear palsy (PSP) and 30 with corticobasal syndrome. These participants were intravenously injected with the same drug (TPI-287 – a microtubule stabilizer) once every 3 weeks for 9 weeks (with an optional 6-week open-label extension).

Although the findings of the study did not support further development of TPI-287 for tauopathies, the overall structure of the study represents an interesting example of how researchers are taking different approaches to investigating neurodegenerative conditions.

In today’s post, we will discuss novel clinical trial designs (“baskets and umbrella”) and other examples of research efforts to better understand neurodegeneration as a whole.

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Source: HuffPost

It was when my daughter turned 3 years old that the psychological warfare really started.

And I remember the moment of realisation very clearly: It began with her desire for a pet dog.

Up until that point in time, she had limited experience with dogs and her negotiation strategies centred solely around crying. I think she loved “the idea” of a dog, but she was generally quite timid around them. Regardless, she gradually began applying pressure (read: lots of crying) on us to get a dog.

And said pressure began to build rapidly (read: frequent episodes of lots of crying).

Source: Focus

Now my wife is definitely not a dog person (“wet, filthy, smelly things“). I on the other hand quite like dogs, but I was utterly, utterly, utterly opposed to getting one because I know full well who will be lumped with the mid-winter late night “walkies” two years down the line: me!

The pressure from our daughter continued to increase, however, until we finally had to sit down with her and explain that we were not going to be getting a dog. On the surface, it looked like she handled this news very well (that is to say: she did not cry). She simply accepted the situation, got up and left the room, saying “Ok”.

My wife and I looked at each other and thought “problem solved”.

The next morning, however, this picture was waiting for us on the kitchen table:

I kid you not.

That’s my daughter and her pet dog (“Linguine“) on the right, and I’m the big, cross-eyed, bad guy on the left.

Since that time the psychological manoeuvring has only become more sophisticated (the teenage years are still a few years away, but I am already absolutely terrified!).

Amusing, but what does this have to do with Parkinson’s?

Continue reading “The basket case”

T-cells: First responders

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The cause of the cell loss and pathology associated with Parkinson’s is still unknown. While the later stages of the condition have been well investigated based on various pathological marker (ie Braak staging), the early manifestations of the condition are still a mystery.

Cells of the immune system are early responders to any signs of trouble in our bodies, and recently researchers have been looking at a specific class of immune cells (called T cells) in postmortem sections of brains from people who passed away with Parkinson’s.

Curiously, in their analysis the researchers found that the bulk of activity of T cells occurs before any cell loss or pathology appears.

In today’s post, we will discuss what T cells are, review the new research, and explore what this could mean for potential therapies for Parkinson’s.

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Your hematopoietic system. Source: Wikipedia

The process of hematopoiesis (or blood formation) is absolutely fascinating.

Seriously.

You start off with a single, multi-potential hematopoietic stem cell. This is called a hemocytoblast (it’s the big cell in middle of the image below):

A hemocytoblast. Source: Pinterest

Given enough time, this single cell will give rise to an entire blood system, made up of many of different types of cells with very specific functions that are required for us to live normal lives.

It is a remarkable achievement of biology.

Understand that at any moment in time your blood system will contain 20-30 trillion cells (in the average human body). And as the image near the top of the post suggests, there are quite a few branches of potential cell types that these blood stem cells can generate.

Very interesting, but what does this have to do with Parkinson’s?

Continue reading “T-cells: First responders”

Is there something in the air?

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Air pollution is an international problem in the post-industrial world. Poor air quality has been associated with an increasing number of medical conditions.

For a long time there has been indications that neurodegenerative conditions – such as Parkinson’s and Alzheimer’s – could also be associated with air pollution.

Recently, several research reports have been published providing compelling evidence further supporting the association and raising new questions. 

In today’s post, we will review some of that research and discuss what could be done next (SPOILER ALERT: the solution involves needing cleaner air).

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Vast. Source: Unequal

I have been extremely fortunate in my life to have travelled to a few of the major cities of the world, but none have had as much impact on me upon arrival as Mexico city.

The pilot had announced over the loud speaker that we were approaching the outskirts of the city, and I looked out of my window to catch a first glimpse of the central American metapolis. Block after block of dwellings passed beneath us, and I thought “great, we’ll be landing soon“.

Mexico City: Really vast. Source: lsecities

Three minutes later, block after block of dwellings were still passing beneath us.

It was the first really vast city that I had ever visited.

Covering approximately 1,500 square kilometers (580 sq miles) of an old volcanic crater, the city is huge. By comparison, New York city covers only 1/2 the area (approximately 780 square kilometers or 300 sq miles – Source).

Home to over 8 million people, Mexico city was an amazing place to explore.

Palacio de Bellas Artes. Source: Turkishairlines

The art, the culture, the history, and the food – lots to see and experience!

Bosque de Chapultepec. Source: Jetsetter

But like all big cities, Mexico city has its share of problems. In addtion to sinking more than 10 metres over the past century (Click here to read more about this), Mexico City also has a terrible air population problem.

And this latter issue has recently been implicated in some Parkinson’s related research.

What do you mean?

Continue reading “Is there something in the air?”

The hunt for a vaccine

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This week, the biotech firm AFFiRiS published the long awaited results of their Phase 1 clinical trial evaluating a vaccine for Parkinson’s. The vaccine – called PD01A – targets a protein that clumps/aggregates together in certain neurons in the brains of people with Parkinson’s.

The multi-year study suggests that the treatment is safe and tolerated. In addition, it causes the immune system to generate antibodies that target the aggregated form of alpha synuclein.

And while it must be remembered that this is a small, open-label study, there are some intriguing statements made in the report.

In today’s post, we will discuss what PD01A is, review the results of the clinical study, and explore what happens next.

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Source: NHI

As the world awaits the development of a vaccine that will combat COVID-19, the neurodegenerative research community has quietly been watching a biotech company in Austria that has been developing a vaccine of a different sort: A vaccine for Parkinson’s.

The company is called AFFiRiS:

Source: Twitter

And this week they published the results of their Phase 1 safety/tolerability clinical trial of their immunotherapy treatment (PD01A) that they are testing in people with recently diagnosed Parkinson’s.

What is immunotherapy?

Continue reading “The hunt for a vaccine”

Guten tag! MODAG

 

Last week the German biotech firm MODAG announced that they had secure €12M in series A funding from various venture capital investors.

The company is going to use those funds to clinically develop their lead compound – Anle138b – in the neurodegenerative condition, Multiple Systems Atrophy (or MSA). 

In today’s post, we will discuss how Anle138b works, what Multiple Systems Atrophy is, and how this news could be good for the Parkinson’s community.

 


Stealth mode. Source: Hackernoon

Last week a small biotech firm in Germany came out of ‘stealth mode’.

What is stealth mode?

According to wikipedia, “in business, stealth mode is a company’s temporary state of secretiveness, usually undertaken to avoid alerting competitors to a pending product launch or other business initiative”.

After years of developing a novel drug, the German company emerged from stealth mode with €12M in series A funding, which will be used to clinically test their new treatment.

The company’s name is MODAG.

And what is MODAG planning to do now they are out of “stealth mode”?

They are planning to clinically test their lead compound which is called Anle138b.

The initial Phase I safety test will be conducted in healthy individuals, but then they will turn their attention to individuals with multiple systems atrophy.

What is Multiple System Atrophy?

Continue reading “Guten tag! MODAG”

“So, will my head glow in a disco?”

 

The clustering (or aggregation) of misfolded proteins is a key feature of many neurodegenerative conditions. These aggregating proteins are collectively referred to as ‘amyloid’ proteins, and the way that they have misfolded allows many copies of these proteins to stick together.

Amyloid proteins are associated with more than 50 medical conditions (from Alzheimer’s, ALS, Huntinton’s and Parkinson’s through to rheumatoid arthritis and diabetes).

In addition to being public enemy no. 1 for their respective conditions, amyloid proteins also share another curious feature:

They glow when exposed to specific wavelengths of light (like near-infrared).

In today’s post, we will look at what we mean by ‘amyloid proteins’, what this new research found, and how this property could be extremely useful in the tracking of Parkinson’s over time.

 


Source: Yoursalesplaybook

If you have recently sent me an email, you may not have had a response. I apologise profusely for this, but I have gradually become inundated with questions and requests, and have had a hard time keeping up (in addition: family and day job take priority).

I do get some wonderfully titled emails though, which immediately grab the attention.

For example, the other day I recieved an email entitled:

“So, will my head glow in a disco?”

A brief glance at the contents confirmed suspicions that the sender was referring to this new research report:

Title: Ultraviolet–visible–near-infrared optical properties of amyloid fibrils shed light on amyloidogenesis
Authors: Pansieri J, Josserand V, Lee S-J, Rongier A, Imbert D, Sallanon MM, Kövari E, Dane TG, Vendrely C, Chaix-Pluchery O, Guidetti M, Vollaire J, Fertin A, Usson Y, Rannou P, Coll J-L, Marquette C, & Forge V
Journal: Nature Photonics, published 13th May 2019
PMID: N/A

Previously researchers have described an intrinsic ultraviolet–visible optical property to amyloid proteins.

What does that mean?

Continue reading ““So, will my head glow in a disco?””

When undruggable becomes druggable

 

Nuclear receptor related 1 protein (or NURR1) is a protein that has been shown to have a powerful effect on the survival of dopamine neurons – a population of cells in the brain that is severely affected by Parkinson’s.

For a long time researchers have been searching for compounds that would activate NURR1, but the vast majority of those efforts have been unsuccessful, leaving some scientists suggesting that NURR1 is “undruggable” (meaning there is no drug that can activate it).

Recently, however, a research report was published which suggests this “undruggable” protein is druggable, and the activator is derived from a curious source: dopamine

In today’s post, we will discuss what NURR1 is, what the new research suggests, and how this new research could be useful in the development of novel therapeutics for Parkinson’s.

 


Source: PPcorn

It always seems impossible until it’s done – Nelson Mandela

In 1997, when Nelson Mandela was stepping down as President of the African National Congress, some researchers in Stockholm (Sweden) published the results of a study that would have a major impact on our understanding of how to keep dopamine neurons alive.

(Yeah, I know. That is a strange segway, but some of my recent intros have dragged on a bit – so let’s just get down to business)

Dopamine neurons are of the one groups of cells in the brain that are severely affected by Parkinson’s. By the time a person begins to exhibit the movement symptoms of the condition, they will have lost 40-60% of the dopamine neurons in a region called the substantia nigra. In the image below, there are two sections of brain – cut on a horizontal plane through the midbrain at the level of the substantia nigra – one displaying a normal compliment of dopamine neurons (on the left) and the other from a person who passed away with Parkinson’s demonstrating a reduction in this cell population (on the right).

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

The researchers in Sweden had made an amazing discovery – they had identified a single gene (a specific region of DNA) that was critical to the survival of dopamine neurons. When they artificially disrupted the section of DNA where this gene lives – an action which resulted in no protein for this gene being produced – it resulted in mice being born with no midbrain dopamine neurons:

Title: Dopamine neuron agenesis in Nurr1-deficient mice
Authors: Zetterström RH, Solomin L, Jansson L, Hoffer BJ, Olson L, Perlmann T.
Journal: Science. 1997 Apr 11;276(5310):248-50.
PMID: 9092472

The researchers who conducted this study found that the mice with no NURR1 protein exhibited very little movement and did not survive long after birth. And this result was very quickly replicated by other independent research groups (Click here and here to see examples)

So what was this amazing gene called?

Nuclear receptor related 1 protein (or NURR1; it is also known as NR4A2 – nuclear receptor subfamily 4, group A, member 2)

And what is NURR1?

Continue reading “When undruggable becomes druggable”

Distinctly human?

 

It is often said that Parkinson’s is a ‘distinctly human’ condition. Researchers will write in their reports that other animals do not naturally develop the features of the condition, even at late stages of life.

But how true is this statement?

Recently, some research has been published which brings into question this idea.

In today’s post, we will review these new findings and discuss how they may provide us with a means of testing both novel disease modifying therapies AND our very notion of what Parkinson’s means.

 


Checking his Tinder account? Source: LSE

Deep philosphical question: What makes humans unique?

Seriously, what differentiates us from other members of the animal kingdom?

Some researchers suggest that our tendency to wear clothes is a uniquely human trait.

The clothes we wear make us distinct. Source: Si-ta

But this is certainly not specific to us. While humans dress up to ‘stand out’ in a crowd, there are many species of animals that dress up to hide themselves from both predator and prey.

A good example of this is the ‘decorator crab’ (Naxia tumida; common name Little seaweed crab). These creatures spend a great deal of time dressing up, by sticking stuff (think plants and even some sedentary animals) to their exoskeleton in order to better blend into their environment. Here is a good example:

Many different kinds of insects also dress themselves up, such as Chrysopidae larva:

Dressed for success. Source: Bogleech

In fact, for most of the examples that people propose for “human unique” traits (for example, syntax, art, empathy), mother nature provides many counters (Humpback whales, bower birds, chickens – respectively).

So why is it that we think Parkinson’s is any different?

Wait a minute. Are there other animals that get Parkinson’s?

Continue reading “Distinctly human?”

Thyme to look east: Baicalein

 

Recently I wrote a post about research investigating an interesting compound called Epigallocatechin gallate (or EGCG – click here for that post). Several eagle-eyed readers, however, noted something interesting in the details of one of the research reports that was discussed in that post.

The study in question had used EGCG as a positive control for evaluating the ability of other compounds for their ability to inhibit the clustering of Parkinson’s-associated protein alpha synuclein.

But there was also a second positive control used in that study.

It is called baicalein.

In today’s post, we will discuss what baicalein is and what research has been done on it in the context of Parkinson’s.

 


Lake Baikal. Source: Audleytravel

Once upon a thyme, in a far away land, there was a mysterious little flowering plant.

The “far away land” was the southern parts of eastern Siberia.

And the flowering plant is Scutellaria baicalensis – which is more commonly referred to as Baikal skullcap.

What is Baikal skullcap?

Baikal skullcap is a perennial herb that is indigenous to Southern Siberia, China and Korea. For centuries, traditional Chinese medicine has used the dried roots – which is called huángqín (Chinese: 黄芩 or golden root) – for a variety of ailments.

Baikal skullcap. Source: Urbol

The plant grows to between 1-4 feet in height, with lance head-shaped leaves and blue-purple flowers. Baikal skullcap belongs to the same family of flowering plants (Lamiaceae) as thyme, basil, mint and rosemary.

For traditional Chinese medicinal use, the roots are usually collected in spring or autumn once the plant is more than 3-4 years old. They are dried and then used to treat hypertension, to reduce “fire and dampness”, and to treat prostate & breast cancers.

And one of the key constituents of Baikal skullcap (and huángqín) is a compound called baicalein.

What is baicalein?

Continue reading “Thyme to look east: Baicalein”

We’re re-branding: It’s now called PARPinson’s

 

A new research report has been published this week which may point not only towards a new understanding of the biology of Parkinson’s, but also to potentially novel therapies which are clinically available.

These exciting new findings involve a DNA repair mechanism called ‘poly ADP ribose polymerase’ (or simply PARP) and a process of cell death called Parthanatos.

Biotech companies have developed PARP inhibitors which have been reported to rescue models of Parkinson’s. With a bit of tweaking, this class of drugs could potentially be re-purposed for Parkinson’s.

In today’s post, we will look at what PARP is, explain how PARP inhibitors work, review what previous PD research has been conducted on this topic, evaluate the new report, and consider what it means for the Parkinson’s community (Spoiler alert: this will be a long post!).

 



Source: Quotefancy

Ah, the good old days!

Remember them. Way back before Netflix. When life was sooo much easier.

You know what I’m talking about.

Back when biology was simple. Remember when DNA gave rise to RNA and RNA gave rise to protein, and that was it. Simpler times they were. Now, everything is so much more complicated. We have all manner of ‘regulatory RNA’, epigentics, splice variants, and let’s not get started on the labyrinthian world of protein folding.

Oh, how I long for the good old days.

Back when a cell could only die one of two ways: apoptosis (a carefully controlled programmed manner of death) and necrosis (cell death by injury):

Source: Researchgate

Now life is too complicated and complex beyond reason or imagination.

Let’s just take the example of cell death that I mentioned above: over the past decade, the Nomenclature Committee on Cell Death (or NCCD – I kid you not there is actually a committee for this) has written up guidelines for the definition/interpretation of ‘cell death’. And as part of that effort they have decided that there are now at least 12 (yes, 12) different ways a cell can die:

Source: Nature

For those of who are interested in reading more about all of these different kinds of cell death, click here to read NCCD committee’s most recent recommendations which were updated this year (2018). Some riveting betime reading.

Which form of cell death applies to Parkinson’s?

Now that’s a really good question!

One that has been studied and the source of debate for a very long time.

To be fair, we don’t really know. But fascinating new research published this week suggests that the Parthanatos pathway could be involved in the cell death associated with Parkinson’s.

What is Parthanatos?

Continue reading “We’re re-branding: It’s now called PARPinson’s”