Biotech firm Denali announced the dosing of the first person in their Phase Ib clinical study of their experimental treatment for Parkinson’s called DNL201.
DNL201 is an inhibitor of a Parkinson’s-associated protein called Leucine-rich repeat kinase 2 (LRRK2).
In Parkinson’s, there is evidence that LRRK2 is over activate, and by inhibiting LRRK2 Denali is hoping to slow the progression of Parkinson’s.
In today’s post, we will discuss what LRRK2 is, what evidence exists for DNL201, and what the new clinical trial will involve.
Founded in 2013, by a group of former Genentech executives, San Francisco-based Denali Therapeutics is a biotech company which is focused on developing novel therapies for people suffering from neurodegenerative diseases. Although they have product development programs for other condition (such as Amyotrophic Lateral Sclerosis and Alzheimer’s disease), Parkinson’s is their primary interest.
And their target for therapeutic effect?
The Parkinson’s-associated protein called Leucine-rich repeat kinase 2 (or LRRK2).
What is LRRK2?
This post is a game of two halves.
The first half will explain the concept of a surgical procedure for Parkinson’s called ‘subthalamic deep brain stimulation‘, in which doctors permenantly implant electrodes into the brain to stimulate a region – the subthalamic nucleus. By stimulating this region with electrical impulses, doctors can provide a better quality of life (in most cases) to people with severe features of Parkinson’s.
In the second half of this post, we will look at an approach to doing the same thing,… but without the electrodes.
Rather, researchers are using gene therapy.
In today’s post, we will discuss what deep brain stimulation is, what gene therapy is, and how the gene therapy approach is having a different kind of impact on the brain to that of deep brain stimulation.
Welcome to the first half of today’s post.
It begins with you asking the question:
What is deep brain stimulation?
Deep brain stimulation (or DBS) is a treatment method that involves embedding electrodes into the brain to help modulate the brain activity involved in movement.
It is a prodcedure that is usually offered to people with Parkinson’s who have excessive tremor or debilitating dyskinesias.
First introduced in 1987, deep brain stimulation consists of three components: the pulse generator, an extension wire, and the leads (which the electrodes are attached to). All of these components are implanted inside the body. The system is turned on, programmed and turned off remotely.
Moving forward into 2019 and beyond, we are going to be getting more sophisticated and targetted with our clinical trials for Parkinson’s. We are gradually moving away from the days when a drug was tested on anyone in the Parkinson’s-affected community, and heading for an age of sub-type specific treatments (Click here for a previous SoPD post on subtyping efforts for PD).
As part of this shift, there are a series of ongoing studies that are trying to identify not only the clinical & biological characteristics of those Parkinson’s sub-types, but also individuals who may already be in those groupings.
One such study is called “Rapsodi” – and it is focused on the identification of people with a particular genetic risk factor of PD – the GBA gene – who also demonstrate the early signs of Parkinson’s.
In today’s post, we will discuss what GBA is, how it is associated with Parkinson’s, and why the Rapsodi study is worthy of the PD community’s attention.
Ambroxol. Source: Skinflint
The clinical trial of Ambroxol in Parkinson’s that has been conducted in London (UK) is close to announcing their final results. The Ambroxol study report should be published in early 2019.
What is the ambroxol study?
Started in February 2017, the Ambroxol study (named AiM-PD – Ambroxol in Disease Modification in Parkinson Disease) is a phase IIA prospective, single-centre, open label clinical trial to evaluate the safety, tolerability and pharmacodynamic effects of Ambroxol in Parkinson’s (Click here to read more about this trial and click here for the press release announcing the start of the study).
This trial, which is funded by the Cure Parkinson’s Trust and the Van Andel Research Institute (USA), has been conducted at the Royal Free Hospital in London (UK). The study has involved 20 people with Parkinson’s self-administering Ambroxol (in 60 mg per tablet) over a 6 month time frame. The participants were given 5 escalating doses of the drug for the first few weeks of the study (from 60 mg three times per day, gradually building up to 420 mg three times a day after the first month of the study).
But hang on a second. What is exactly is Ambroxol?
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?
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 2018.
The post is divided into five parts based on the type of research (Basic biology, disease mechanism, clinical research, other news, and Review articles/videos).
So, what happened during November 2018?
In world news:
4th November – Kiwi Mike Lloyd finished his 10th New York marathon! Diagnosed with Parkinson’s 6 years ago, his story is truly inspiring – “To me it’s a celebration of what I can do, & what we can do as people, rather than what we can’t do”
Oh, and did I mention he’s also blind?
6th November – Mining company BHP suspended all rail operations in Western Australia after a train (consisting of 4 locomotives & 268 wagons) ladened with iron ore travelled over 92km (57miles) with no driver on board. It was finally deliberately derailed by the authorities. And that’s not the only crazy story out of Australia this month – check out Knickers the giant steer!
9th November – Supermarket Iceland had their Christmas advert banned in the UK because it was “deemed to breach political advertising rules” (Can anyone please explain to me why? I quite liked it):
11th November – New Zealand space company ‘Rocket Lab‘ announced the successful orbital launch and deployment of customer satellites – their first commercial project, named ‘It’s Business Time’ – at 16:50 NZDT (03:50 UTC – Click here for the press release). Little old NZ punching above its weight yet again. The launch can be seen from 20 minutes into this video:
22nd November – Engineers at the Massachusetts Institute of Technology announced that they have developed a model aircraft with no moving parts that is capable of flight. The age of ionic wind has begun.
In the world of Parkinson’s research, a great deal of new research and news was reported:
In November 2018, there were 762 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (7172 for all of 2018 so far – we should easily beat last years total of 7644). In addition, there was a wave to news reports regarding various other bits of Parkinson’s research activity (clinical trials, etc).
The top 8 pieces of Parkinson’s news
Inflammation is part of the immune system’s response to damage or infection. It is a very natural process that our bodies undergo when we come into harms way.
Researchers at the University of Queensland, have recently demonstrated something interesting about the inflammation associated with Parkinson’s: by inhibiting a very specific part of the inflammatory process, they can reduce the spread of Parkinson’s associated alpha synuclein pathology in models of PD.
And they have developed a drug – called MCC950 – that specifically targets that component of the inflammation process which they are now seeking to test in clinical trials.
In today’s post, we will discuss what inflammation is, review this new research, and consider what it could all mean for the Parkinson’s community.
Spot the unhealthy cell – exhibiting signs of stress (yellow). Source: Gettyimages
No silly preamble today – this is going to be a very long post, so we’re diving straight in:
When cells in your body are stressed or sick, they begin to release messenger proteins which inform the rest of your body that something is wrong.
When enough cells release these messenger proteins, it can cause inflammation.
What is inflammation?
Inflammation is a vital 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, 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 the level of messenger proteins being released partly depends on multi-protein structures called inflammasomes.
What are inflammasomes?
On the 12th and 13th November, Parkinson’s UK held their biennial research conference in York.
It is not only an opportunity for the charity to showcase some of the research that they have funded over the last few years, but it was also a chance for members of the Parkinson’s research community to come together to share ideas, network and form new collaborations.
I was lucky enough to attend the event this year, and wanted to share some of the take away messages from the conference with the readers.
In today’s post, we will review Parkinson’s UK 2018 research conference (#Parkinsons2018).
Parkinson’s UK is the largest Parkinson’s research and support charity in the United Kingdom. Since 2015, they have invested over £18 million in a variety of research projects focused on all aspects of Parkinson’s – from new experimental treatments to the Parkinson’s UK Brain Bank.
Every two years, Parkinson’s UK holds a conference highlighting some of the research that the organisation has funded over the last few years. The meeting is usually held in the beautiful walled city of York – lots of history and narrow streets to explore.
Th “The Shambles” in York. Source: hauntedrooms
The SoPD has a policy of not advertising or endorsing products/services.
This rule is in place to avoid any ethical/conflict of interest situations. It does little, however, to stop folks from bombarding the comments sections with links for wondrous magical cures which probably involve more ‘magical’ than actual cure.
Having said all that, every now and then I find or read about something that I think may be of interest to readers. In many of those cases, I can not vouch for the information being provided, but where I think there is the potential to stimulate the imagination of the reader, I am happy to take a chance and share it.
Today’s post is all about one such case: Not impossible labs.
The first character in this story is a graffiti artist.
His name is Tony ‘Tempt’ Quan.
Tempt grew up in east Los Angeles, painting his name and art across the city from the 1980s onwards. He became the stuff of myth and legend – one of the most influential figures in the graffiti scene in California for a generation.
But that all changed in 2003, when – at 34 years of age – Tempt was diagnosed with Amyotrophic Lateral Sclerosis (or ALS).
Also known as motor neurone disease or Lou Gehrig’s disease, ALS is a neurodegenerative condition that leaves the sufferer completely paralysed. There are only two FDA-approved drugs for the treatment of ALS, but they have little if any impact on disease course.
For 6 years, Tempt lay paralysed and did not produce a single piece of art.
And that was when the second character in this story appeared.
His name was Mick Ebeling.
Researchers are building as ever increasing amount of evidence supporting the idea that as our bodies age, there is an accumulation of cells that cease to function normally. But rather than simply dying, these ‘non-functional’ cells shut down and enter a state which is refered to as ‘senescence‘.
And scientists have also discovered that these senescent cells are not completely dormant. They are still active, but their activity can be of a rather negative flavour. And new research from the
The good new is that a novel class of therapies are being developed to deal with senescent cells. These new drugs are called senolytics.
In today’s post, we will discuss what is meant by senescence, we will review the new data associated with Parkinson’s, and we will consider some of the interesting senolytic approaches that could be useful for PD.
This is not my living room… honest. Source: Youtube
Humans being are great collectors.
We may not all be hoarders – as in the image above – but everyone has extra baggage. Everybody has stuff they don’t need. And the ridiculous part of this equation is that some of that stuff is kept on despite the fact that it doesn’t even work properly any more.
The obvious question is:
Oh, and don’t get me wrong – I’m not talking about all that junk you have lying around in your house/shed.
No, I’m referring to all the senescent cells in your body.
Huh? What are senescent cells?
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!).
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):
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:
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?