Clinical trials: The Power of One

As the age of personalised medicine approaches, innovative researchers are rethinking the way we conduct clinical studies. “Rethinking” in radical ways – think: individualised clinical trials! 

One obvious question is: Can you really conduct a clinical trial involving just one participant?

In this post, we will look at some of the ideas and evaluate the strengths and weaknesses these approaches.


A Nobel prize medal. Source: Motley

In the annals of Nobel prize history, there are a couple winners that stands out for their shear….um, well,…audacity.

One example in particular, was the award given to physician Dr Werner Forssmann. In 1956, Andre Cournand, Dickinson Richards and Forssmann were awarded the Nobel Prize in Physiology or Medicine “for their discoveries concerning heart catheterisation and pathological changes in the circulatory system”. Forssmann was responsible for the first part (heart catheterisation).

Source: Nobelprize

In 1929, at the age of 25, Forssmann performed the first human cardiac catheterisation – that is a procedure that involves inserting a thin, flexible tube directly into the heart via an artery (usually in the arm, leg or neck). It is a very common procedure performed on a daily basis in any hospital today. But in 1929, it was revolutionary. And the audacious aspect of this feat was that Forssmann performed the procedure on himself!

And if you think that is too crazy to be true, please read on.

But be warned: this particular story gets really bonkers.

Continue reading “Clinical trials: The Power of One”

“Three hellos” for Parkinson’s

Trehalose is a small molecule – nutritionally equivalent to glucose – that helps to prevent protein from aggregating (that is, clustering together in a bad way).

Parkinson’s disease is a neurodegenerative condition that is characterised by protein aggregating, or clustering together in a bad way.

Is anyone else thinking what I’m thinking?

In today’s post we will look at what trelahose is, review some of the research has been done in the context of Parkinson’s disease, and discuss how we should be thinking about assessing this molecule clinically.


Neuropathologists examining a section of brain tissue. Source: Imperial

When a neuropathologist makes an examination of the brain of a person who passed away with Parkinson’s, there are two characteristic hallmarks that they will be looking for in order to provide a definitively postmortem diagnosis of the condition:

1.  The loss of dopamine producing neurons in a region of the brain called the substantia nigra.

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The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source:Memorangapp

2.  The clustering (or ‘aggregation’) of a protein called alpha synuclein. Specifically, they will be looking for dense circular aggregates of the protein within cells, which are referred to as Lewy bodies.

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

Alpha-synuclein is actually a very common protein in the brain – it makes up about 1% of the material in neurons (and understand that there are thousands of different proteins in a cell, thus 1% is a huge portion). For some reason, however, in Parkinson’s disease this protein starts to aggregate and ultimately forms into Lewy bodies:

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

In addition to Lewy bodies, the neuropathologist may also see alpha synuclein clustering in other parts of affected cells. For example, aggregated alpha synuclein can be seen in the branches of cells (these clusterings are called ‘Lewy neurites‘ – see the image below where alpha synuclein has been stained brown on a section of brain from a person with Parkinson’s disease.

Lewy_neurites_alpha_synuclein

Examples of Lewy neurites (indicated by arrows). Source: Wikimedia

Given these two distinctive features of the Parkinsonian brain (the loss of dopamine neurons and the aggregation of alpha synuclein), a great deal of research has focused on A.) neuroprotective agents to protect the remaining dopamine-producing neurons in the substantia nigra, and B.) compounds that stop the aggregation of alpha synuclein.

In today’s post, we will look at the research that has been conducted on one particular compounds that appears to stop the aggregation of alpha synuclein.

It is call Trehalose (pronounces ‘tray-hellos’).

Continue reading ““Three hellos” for Parkinson’s”

Are we getting NURR to the end of Parkinson’s disease?

Nuclear receptor related 1 protein (or NURR1) is a protein that is critical to the development and survival of dopamine neurons – the cells in the brain that are affected in Parkinson’s disease.

Given the importance of this protein for the survival of these cells, a lot of research has been conducted on finding activators of NURR1.

In today’s post we will look at this research, discuss the results, and consider issues with regards to using these activators in Parkinson’s disease.


Comet Hale–Bopp. Source: Physics.smu.edu

Back in 1997, 10 days after Comet Hale–Bopp passed perihelion (April 1, 1997 – no joke; perihelion being the the point in the orbit of a comet when it is nearest to the sun) and just two days before golfer Tiger Woods won his first Masters Tournament, 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.

Dopamine neurons are one group of cells in the brain that are severely affected by Parkinson’s disease. 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 and the other from a person who passed away with Parkinson’s demonstrating a reduction in this cell population.

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The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source:Memorangapp

The researchers in Sweden had made an amazing discovery – they had identified a single gene that was critical to the survival of dopamine neurons. When they artificially mutated the section of DNA where this gene lives – an action which resulted in no protein for this gene being produced – they generated genetically engineered mice with no 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 research groups (Click here and here to see examples)

So what was this amazing gene called?

Continue reading “Are we getting NURR to the end of Parkinson’s disease?”

Resveratrol’s neglected siblings

 

We have previously discussed the powerful antioxidant Resveratrol, and reviewed the research suggesting that it could be beneficial in the context of Parkinson’s disease (Click here to read that post).

I have subsequently been asked by several readers to provide a critique of the Parkinson’s-associated research focused on Resveratrol’s twin sister, Pterostilbene (pronounced ‘Terra-still-bean’).

But quite frankly, I can’t.

Why? Because there is NO peer-reviewed scientific research on Pterostilbene in models of Parkinson’s disease.

In today’s post we will look at what Pterostilbene is, what is known about it, and why we should seriously consider doing some research on this compound (and its cousin Piceatannol) in the context of Parkinson’s disease.


Blue berries are the best natural source of Pterostilbene. Source: Pennington

So this is likely to be the shortest post in SoPD history.

Why?

Because there is nothing to talk about.

There is simply no Parkinson’s-related research on the topic of today’s post: Pterostilbene. And that is actually a crying shame, because it is a very interesting compound.

What is Pterostilbene?

Like Resveratrol, Pterostilbene is a stilbenoid.

Stilbenoids are a large class of compounds that share the basic chemical structure of C6-C2-C6:

Resveratrol is a good example of a stilbenoid. Source: Wikipedia

Stilbenoids are phytoalexins (think: plant antibiotics) produced naturally by numerous plants. They are small compounds that become active when the plant is under attack by pathogens, such as bacteria or fungi. Thus, their function is generally considered to part of an anti-microbial/anti-bacterial plant defence system for plants.

The most well-known stilbenoid is resveratrol which grabbed the attention of the research community in a 1997 study when it was found to inhibit tumour growth in particular animal models of cancer:

Continue reading “Resveratrol’s neglected siblings”

Trying to ‘beet’ Parkinson’s in the developing world

Recently I discussed my ‘Plan B’ idea, which involves providing a cheap alternative to expensive drugs for folks living in the developing world with Parkinson’s (Click here for that post).

While doing some research for that particular post, I came across another really interesting bit of science that is being funded by Parkinson’s UK.

It involves Beetroot.

In today’s post we will look at how scientists are attempting turn this red root vegetable into a white root vegetable in an effort to solve Parkinson’s in the developing world.


Pompeii and Mount Vesuvius. Source: NationalGeo

During visits to the ancient Roman city of Pompeii (in Italy), tourists are often drawn by their innocent curiosity to the ‘red light’ district of the city. And while they are there, they are usually amused by the ‘descriptive’ murals that still line the walls of the buildings in that quarter.

So amused in fact that they often miss the beetroots.

Huh? Beetroots?

Yes, beetroots.

I’m not suggesting that anyone spends a great deal of time making a close inspection of the walls, but if you look very carefully, you will often see renditions of beetroots.

They are everywhere. For example:

Two beetroots hanging from the ceiling.

Again: Huh?

The Romans considered beetroot to be quite the aphrodisiac, believing that the juice ‘promoted amorous feelings’. They also ate the red roots for medicinal purposes, consuming it as a laxative or to cure fever.

And this medicinal angle lets me segway nicely into the actual topic of today’s post. You see, in the modern era researcher are hoping to use beetroot for medicinal purposes again. But this time, the beetroot will be used to solve an issue close to my heart: treating people with Parkinson’s in the developing world.

Using beetroot to treat Parkinson’s?

Continue reading “Trying to ‘beet’ Parkinson’s in the developing world”

PACAP and a snail model of Parkinson’s

We are going to talk about a snail model of Parkinson’s disease. I kid you not.

Love them or hate them, recent research on snails is helping us to better understand a potential therapeutic target for Parkinson’s disease, called Pituitary adenylate cyclase-activating polypeptide (or PACAP).

In today’s post we will look at what PACAP is, outline the new snail research, and discuss what they mean for people living with Parkinson’s disease.


Snail2

The humble snail. Source: Warrenphotographic

In a recent post, I talked about a class of drugs called Dipeptidyl peptidase-4 (or DPP-4) inhibitors (Click here to read that post). DPP-4 is a ubiquitous enzyme (it is present on most cells in your body) that breaks down certain proteins.

In that post, I listed some of the proteins that DPP-4 targets – they include:

  • Gastrin-releasing peptide (GRP)
  • Glucagon
  • Glucagon-like peptide-1 (GLP-1)
  • Glucagon-like peptide-2 (GLP-2)
  • Granulocyte-macrophage colony-stimulating factor (GM-CSF)
  • GHRH and IGF-1
  • High-mobility group box 1 (HMGB1)
  • Macrophage-derived chemokine (MDC)
  • Macrophage inflammatory protein-1 α (MIP-1 α), chemokine (C-C motif) ligand 3-like 1 (CCL3L1), or LD78β
  • Pituitary adenylate cyclase-activating polypeptide (PACAP)
  • Neuropeptide Y (NPY)
  • Regulated on activation, normal T cell expressed and secreted (Rantes)
  • Stromal cell-derived factor-1 (SDF-1)
  • Substance P (SP)

Lots of interesting proteins with regards to Parkinson’s disease on this list, including GLP-1 which has been turned in the drug Exenatide (which has demonstrated positive effects in recent clinical trials for Parkinson’s disease – click here and here to read more about this). Another interesting protein on the list is ‘Granulocyte-macrophage colony-stimulating factor‘ (GM-CSF) which we have also discussed in a previous post (Click here to read that post). A synthetic version of GM-CSF (called Sargramostim) has recently been tested in a clinical trial of Parkinson’s disease in Nebraska, and the results of that Phase I trial have been very encouraging.

By treating people with DPP-4 inhibitors (also known as ‘gliptins’), one would be blocking the breaking down of these potentially beneficial proteins – increasing the general amount of GLP-1 and GMCSF that is floating around in the body.


EDITOR’S NOTE: DPP-4 inhibitors have not yet been clinically tested in Parkinson’s disease, and thus we have no idea if they are safe in people with this condition. They are being mentioned here purely as part of an academic discussion.


One protein on the list of DPP-4 targets above that we have not yet discussed is Pituitary adenylate cyclase-activating polypeptide (or PACAP).

And today we are going to have a look at it.

Why?

Continue reading “PACAP and a snail model of Parkinson’s”

A clever new Trk for Rasagiline

The protein Alpha Synuclein has long been considered the bad-boy of Parkinson’s disease research. Possibly one of the main villains in the whole scheme of things. 

New research suggests that it may be interfering with a neuroprotective pathway, leaving the affected cell more vulnerable to stress/toxins. But that same research has highlighted a novel beneficial feature of an old class of drugs: MAO-B inhibitors.

In today’s post we will outline the new research, discuss the results, and look at whether this new Trk warrants a re-think of MAO-B inhibitors.


The great Harry Houdini. Source: Wikipedia

I’m not sure about you, but I enjoy a good magic trick.

That exhilarating moment when you are left wondering just one thing: How do they do that?

(Seriously, at 4:40 a baguette comes out of thin air – how did he do that?)

Widely believed to have been one of the greatest magicians of all time (Source), Harry Houdini is still to this day revered among those who practise the ‘dark arts’.

Born Erik Weisz in Budapest (in 1874), Houdini arrived in the US in 1878. Fascinated with magic, in 1894, he launched his career as a professional magician and drew attention for his daring feats of escape. He renamed himself “Harry Houdini” – the first name being derived from his childhood nickname, “Ehrie,” and the last name paying homage to the great French magician Jean Eugène Robert-Houdin. In 1899, Houdini’s act caught the eye of Martin Beck, an entertainment manager, and from there the rest is history. Constantly upping the ante, his feats became bolder and more death defying.

And the crowds loved him.

From stage, he moved on to film – ultimately starting his own production company, Houdini Picture Corporation. In addition, he was a passionate debunker of psychics and mediums, his training in magic helping him to expose frauds (which turned him against his former friend Sir Arthur Conan Doyle, who believed deeply in spiritualism).

This is all very interesting, but what does any of it have to do with Parkinson’s?

Continue reading “A clever new Trk for Rasagiline”

NIX-ing the PARKIN and PINK1 problem

In American slang, to ‘nix‘ something is to ‘put an end to it’.

Curiously, a protein called NIX may be about to help us put an end to Parkinson’s disease, at least in people with specific genetic mutations.

In today’s post we will look at what NIX is, outline a new discovery about it, and discuss what this new information will mean for people living with Parkinson’s disease.


Sydney harbour. Source: uk.Sydney

Before we start, I would like the reader to appreciate that I am putting trans-Tasman rivalry side here to acknowledge some really interesting research that is being conducted in Australia at the moment.

And this is really interesting.

I have previously spoken a lot about mitochondria and Parkinson’s on this website. For the uninitiated, mitochondria are the power house of each cell. They help to keep the lights on. Without them, the party is over and the cell dies.

Mitochondria

Mitochondria and their location in the cell. Source: NCBI

You may remember from high school biology class that mitochondria are tiny bean-shaped objects within the cell. They convert nutrients from food into Adenosine Triphosphate (or ATP). ATP is the fuel which cells run on. Given their critical role in energy supply, mitochondria are plentiful (some cells have thousands) and highly organised within the cell, being moved around to wherever they are needed.

Like you and I and all other things in life, however, mitochondria have a use-by date.

As mitochondria get old and worn out (or damaged) with time, the cell will recycle them via a process called mitophagy (a blending of the words mitochondria and autophagy – the waste disposal system of each cell).

What does this have to do with Parkinson’s disease?

Well, about 10% of Parkinson’s cases are associated with particular genetic variations that render people vulnerable to developing the condition. Some of these mutations are in sections of DNA (called genes) that provide the instructions for proteins that are involved in the process of mitophagy. Two genes, in particular, are the focus of a lot of Parkinson’s-related research – they are called PARKIN and PINK1.

What do PARKIN and PINK1 do?

Continue reading “NIX-ing the PARKIN and PINK1 problem”