In 2013, a biotech company called Ceregene reported disappointing results from their experimental gene therapy clinical trial for Parkinson’s. The data from the study suggested that the therapy had no clinical effect on the progression of Parkinson’s (Click here to read the press release).
Today, however, researchers associated with that biotech company have published a new report that suggests that the treatment had beneficial effects in the brain, but not enough of it was delivered.
The treatment was a gene therapy approach (which involves using DNA rather than drugs to treat medical conditions), and it involved a protein called neurturin.
In today’s post, we will discuss what neurturin is, we will review what this new study found, and consider what the implications could be for future gene therapy trials in Parkinson’s.
Reanalysing clinical trial data (called post-hoc analysis) provides a very useful way of generating new hypotheses even if the initial study did not reach its primary endpoint (that is to say the study did not demonstrate a successful outcome. Post-hoc analysis must be handled carefully, as the findings of such investigations can be viewed as selective ‘cherry picking’ of interesting outcomes. They will need to be tested to determine if they are real effects.
Even more important than post-hoc analysis, however, is following up participants who took part in a trial to see if there were any long-term benefits from the treatment. I often wonder how much important data is lost after a clinical trial simply becomes there is no long term follow up and study investigators lose track of participants as they drift away.
Precious nuggets of information can be gained from long-term analysis. And this week we saw a really interesting example of this.
Here is the research report:
Title: Long-term post-mortem studies following neurturin gene therapy in patients with advanced Parkinson’s disease.
Authors: Chu Y, Bartus RT, Manfredsson FP, Olanow CW, Kordower JH.
Journal: Brain. 2020 Mar 1;143(3):960-975.
PMID: 32203581 (This report is OPEN ACCESS if you wouldl like to read it)
In this study, the researchers were looking at postmortem brain sections from 2 participants who took part in a clinical trial investigating a treatment called neurturin.
What is neurturin?
Given that the condition is defined by the loss of specific types of neurons in the brain, any future therapy for Parkinson’s should include some form of restorative treatment. Much of the current clinical research exploring restoration in Parkinson’s is focused on cell transplantation – replacing the cells that have been lost in the brain.
But the adult brain is very different to the developing brain. While youngsters have lots of nurturing and supportive protein floating around – encouraging plasticity and survival – once we reach adulthood, our brains appear to be full of inhibitory molecules that reduce rejuvenation in the case of injury.
What if we could re-introduce some of those supportive factors and remove the inhibitory proteins? Could this help with restorative therapies for Parkinson’s?
In today’s post, we will look at new research exploring how we may be able to reduce some of those inhibitory factors and provide a more supportive environment for restorative therapy in Parkinson’s.
As we regularly state here on the SoPD, any ‘curative therapy’ for Parkinson’s is going to require three core components:
- A disease halting mechanism
- A neuroprotective agent
- Some form of restorative therapy
Now, the bad news is (as far as I am aware) there is no single treatment currently available (or being tested) that can do all three of these things. By this I mean that there is no disease halting mechanism therapy that can also replace lost brain cells. Nor is there a restorative therapy that stop the progression of the condition.
That statement can obviously be read as bad news, but it shouldn’t.
Let me explain:
A curative therapy for Parkinson’s is going to need to be personalised to each individual, with varying levels of each of the three component listed above. It will be a multi-modal approach designed for each individual’s needs.
Making things personal. Source: Flickr
By this I mean, there is a great deal of heterogeneity (or variability) between individuals with regards to their symptoms and the amount of time that they have had the condition. Some folks are more tremor dominant, while others do not experience tremor at all. Likewise, some individuals have only just been diagnosed, while others have lived with the condition for many years.
The treatment needs of each individual will be different, and thus what we will require is different amounts of the disease halting mechanism component, the neuroprotection component, and the restorative therapy components for each affected person.
In today’s post we are going to explore some alternative approaches being tested for restorative therapy.
What do you mean ‘alternative’?
Neurotrophic factors are naturally occuring proteins that help to keep neurons alive, provide a supportive environment, and encourage growth.
For a long time, researchers have been exploring methods of utilising the power of neurotrophic factors in regenerative strategies for neurodegenerative conditions, like Parkinson’s.
Today, the biotech firm Herantis Pharma announced topline results of their Phase 1/2 clinical trial of the neurotrophic factor Cerebral Dopamine Neurotrophic Factor (or CDNF).
In today’s short post, we discuss what CDNF is, explore what the trial involved, and consider what the
It is cold this time of year in Helsinki, but there will be some warm smiles there today.
A small biotech firm called Herantis Pharma has announced the topline results of their Phase 1/2 clinical trial exploring the safety and tolerability of a treatment called CDNF.
What is CDNF?
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:
Things were a bit quiet on the SoPD over the summer, but for good reasons. There was a short hiatus for a family break, but the rest of the time I was rather occupied with the day job. Tremendous efforts were being made at the Cure Parkinson’s Trust, as we were gearing up for our main event of the year: the Linked Clinical Trials (LCT) meeting.
This is an annual meeting at which 20 Parkinson’s experts from around the world, gather for a two day face-to-face pow-wow. They evaluate dossiers which contain everything we know about 20+ compounds which have exhibited potential for disease modification in Parkinson’s. The goal of the committee is to decide which of them is ready for clinical evaluation.
The writing of those LCT dossiers is a year long exercise, which inevitably becomes a bit of a panic in June and July (hence the lack of activity here at SoPD HQ during that period). It is a mammoth, marathon task, but as you shall see it is one that I rather like.
In today’s post, we will discuss what the Linked Clinical Trials initiative is, the process behind the project, and some of the progress being made by the programme.
Archimedes. Source: Lecturesbureau
Archimedes of Syracuse (287 BC – 212 BC) the ancient Greek mathematician, once said that the “shortest distance between two points is a straight line“.
My dad (who is not a regular readers of this blog, but is possibly on par with Archie – just in case he does ever read this) has often been heard saying “Just get to the point Simon“.
Millennia apart, but their collective wisdom is same: Ignore everything else, and get straight to the heart of the matter as quickly as you can.
And this is one of the aspect I really like about the Linked Clinical Trials initiative.
It is all about getting to potentially disease modifying treatments for Parkinson’s to the community as quickly as possible.
What is the Linked Clinical Trials programme?
Glial cell-line derived neurotrophic factor (or GDNF) has been a topic of heated discussion in the Parkinson’s community for a long time. Most recently due to the announcement of the results of the Phase II Bristol GDNF clinical trial results, which did not meet the primary end points of the study (Click here to read more about that).
This week at the annual American Association of Neurological Surgeons conference in San Diego, the results of another GDNF clinical trial were presented.
This new study was a Phase I study assessing the safety and tolerability of a gene therapy approach for GDNF in people with Parkinson’s.
In today’s post, we will discuss what gene therapy is, what the new trial results indicate, and what the researchers may be planning to do next for this new clinical trial programme.
Every year members of the American Association of Neurological Surgeons gather together in one spot and compare data/research/clinical notes.
This year the 87th AANS Annual Scientific Meeting was held in spectacular San Diego.
San Diego. Source: AFP
From Saturday 13th April through till Wednesday 17th, clinicians and researchers attended lectures and discussed new data on every aspect of neurological surgery. While I did not (nor planned to) attend the meeting, I was very interested to learn more about one particular presentation.
It involved the announcement of the results of a clinical trial which was focused on a gene therapy approach for Parkinson’s.
The treatment involved GDNF (Click here to read the abstract).
What is GDNF?
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.
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.
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?
Today – 27th February, 2019 – the long-awaited results of the Phase II GDNF clinical trial were published.
GDNF (or glial cell line-derived neurotrophic factor) is a protein that our bodies naturally produce to nurture and support cells. Extensive preclinical research suggested that this protein was particularly supportive of dopamine neurons – a group of cells in the brain that are affected by Parkinson’s.
The results of the Phase II clinical trial suggest that the treatment was having an effect in the brain (based on imaging data), but the clinic-based methods of assessment indicated no significant effect between the treatment and placebo groups.
In today’s post we will look at what GDNF is, review the previous research on the protein, discuss the results of the latest study, and look at what happens next.
And be warned this is going to be a long post!
Boulder, Colorado. Source: Rps
It all began way back in 1991.
George H. W. Bush was half way into his presidency, a rock band called Nirvana released their second album (‘Nevermind’), Michael Jordan and the Chicago Bulls rolled over the LA Lakers to win the NBA championship, and Arnold Schwarzenegger’s ‘Terminator 2’ was the top grossing movie of the year.
But in the city of Boulder (Colorado), a discovery was being made that would change Parkinson’s research forever.
In 1991, Dr Leu-Fen Lin and Dr Frank Collins – both research scientists at a small biotech company called Synergen, isolated a protein that they called glial cell-derived neurotrophic factor, or GDNF.
And in 1993, they shared their discovery with the world in this publication:
Title: GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons.
Authors: Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F.
Journal: Science, 1993 May 21;260(5111):1130-2.
For the uninitiated among you, when future historians write the full history of Parkinson’s, there will be no greater saga than GDNF.
In fact, in the full history of medicine, there are few experimental treatments that people get more excited, divided, impassioned and evangelical than GDNF.
This ‘wonder drug’ has been on a rollercoaster ride of a journey.
What exactly is GDNF?
On Saturday 7th January, 2018, one of the world’s largest pharmaceutical companies – Pfizer – announced that it was abandoning research efforts focused on finding new drugs for Alzheimer’s and Parkinson’s.
Naturally, the Parkinson’s and Alzheimer’s communities reacted with disappointment to the news, viewing it as a demoralising tragedy. And there was genuine concern that other pharmaceutical companies would follow suit in the wake of this decision.
Those fears, however, are unfounded.
In today’s post we will look at some of the reasons underlying Pfizer’s decision, why our approach to failure is wrong, why Pfizer will definitely be back, and what the Parkinson’s community can do about it all.
1. Our approach to failure
Matthew Syed. Source: Amazon
In the first chapter of his book, Syed makes comparisons between the way the aviation industry and the medical profession approach failure, pointing out the processes that follow situations when a disasters occur. In the aviation industry, when any event occurs there is a major investigative process that starts with the recovery of the black boxes. The aviation industry uses this system of investigation to learn from every single incident. It makes the information available to all and this helps with re-thinking everything from cockpit ergonomics and design to air traffic controller procedures. Even the airline companies are keen to be seen to be involved in this process of investigation. Failure, while unfortunate, is not shameful or stigmatising, but rather embraced and enlightening.
In addition, Syed points out that when an airline pilot sits down in his/her cockpit, their neck is also on the line if something goes wrong. Thus, it is in their best interest that the flight should be successful. And this is another reason why the aviation industry takes the reporting of failure so seriously. Everyone benefits from learning from previous situations. And all of this comes together with the observation that 2017 was the safest year on record for flying (based on deaths/flights – Source).
The great ice hockey player Wayne Gretzky once said “A good hockey player plays where the puck is. A great hockey player plays where the puck is going to be” (the original quote actually came from his father, Walter).
At the start of each year, it is a useful practise to layout what is planned for the next 12 months. This can help us better anticipate where ‘the puck’ will be, and allow us to prepare for things further ahead.
2017 was an incredible year for Parkinson’s research, and there is a lot already in place to suggest that 2018 is going to be just as good (if not better).
In this post, we will lay out what we can expect over the next 12 months with regards to the Parkinson’s-related clinical trials research of new therapies.
Charlie Munger (left) and Warren Buffett. Source: Youtube
Many readers will be familiar with the name Warren Buffett.
The charming, folksy “Oracle of Omaha” is one of the wealthiest men in the world. And he is well known for his witticisms about investing, business and life in general.
Warren Buffett. Source: Quickmeme
He regularly provides great one liners like:
“We look for three things [in good business leaders]: intelligence, energy, and integrity. If they don’t have the latter, then you should hope they don’t have the first two either. If someone doesn’t have integrity, then you want them to be dumb and lazy”
“Work for an organisation of people you admire, because it will turn you on. I always worry about people who say, ‘I’m going to do this for ten years; and if I really don’t like it very much, then I’ll do something else….’ That’s a little like saving up sex for your old age. Not a very good idea”
“Choosing your heroes is very important. Associate well, marry up and hope you find someone who doesn’t mind marrying down. It was a huge help to me”
Mr Buffett is wise and a very likeable chap.
Few people, however, are familiar with his business partner, Charlie Munger. And Charlie is my favourite of the pair.