This week Denali Therapeutics released the results of a phase I clinical trial of their primary product, called DNL-201.
DNL-201 is a LRRK2 inhibitor that the company is attempting to take to the clinic for Parkinson’s disease.
In today’s post we will look at what LRRK2 is, how an inhibitor might help in Parkinson’s, and what the results of the trial actually mean.
Denali. Source: Wikipedia
Denali (Koyukon for “the high one”; also known as Mount McKinley) in Alaska is the highest mountain peak in North America, with a summit elevation of 20,310 feet (6,190 m) above sea level. The first verified ascent to Denali’s summit occurred on June 7, 1913, by four climbers Hudson Stuck, Harry Karstens, Walter Harper, and Robert Tatum.
Tatum (left), Karstens (middle), and Harper (right). Source: Gutenberg
Robert Tatum later commented, “The view from the top of Mount McKinley is like looking out the windows of Heaven!”
More recently another adventurous group associated with ‘Denali’ have been trying to scale lofty heights, but of a completely different sort from the mountaineering kind.
In the 1990, scientists identified some fruits that they suspected could give people Parkinson’s.
These fruit are bad, they reported.
More recently, researchers have identified chemicals in that exist in those same fruits that could potential be used to treat Parkinson’s.
These fruit are good, they announce.
In today’s post, we will explain why you should avoid eating certain members of the Annonaceae plant family and we will also look at the stream of research those plants have given rise to which could provide a novel therapy for Parkinson’s.
Guadeloupe. Source: Bluefoottravel
In the late 1990s, researchers noticed something really odd in the French West Indies.
It had a very strange distribution of Parkinsonisms.
What are Parkinsonisms?
‘Parkinsonisms’ refer to a group of neurological conditions that cause movement features similar to those observed in Parkinson’s disease, such as tremors, slow movement and stiffness. The name ‘Parkinsonisms’ is often used as an umbrella term that covers Parkinson’s disease and all of the other ‘Parkinsonisms’.
Parkinsonisms are generally divided into three groups:
- Classical idiopathic Parkinson’s disease (the spontaneous form of the condition)
- Atypical Parkinson’s (such as multiple system atrophy (MSA) and Progressive supranuclear palsy (PSP))
- Secondary Parkinson’s (which can be brought on by mini strokes (aka Vascular Parkinson’s), drugs, head trauma, etc)
Some forms of Parkinsonisms that at associated with genetic risk factors, such as juvenile onset Parkinson’s, are considered atypical. But as our understanding of the genetics risk factors increases, we may find that an increasing number of idiopathic Parkinson’s cases have an underlying genetic component (especially where there is a long family history of the condition) which could alter the structure of our list of Parkinsonisms.
So what was happening in the French West Indies?
One of the cardinal features of the Parkinsonian brain are dense, circular clusters of protein that we call ‘Lewy bodies’.
But what exactly are these Lewy bodies?
How do they form?
And what function do they serve?
More importantly: Are they part of the problem – helping to cause of Parkinson’s? Or are they a desperate attempt by a sick cell to save itself?
In today’s post, we will have a look at new research that makes a very close inspection of Lewy bodies and finds some interesting new details that might tell us something about Parkinson’s.
Neuropathologists conducting a gross examination of a brain. Source: NBC
A definitive diagnosis of Parkinson’s disease can only be made at the postmortem stage with an examination of the brain. Until that moment, all cases of Parkinson’s disease 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).
The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source:Memorangapp
2. Dense, circular clusters (or aggregates) of protein within cells, which are called Lewy bodies.
A cartoon of a neuron, with the Lewy body indicated within the cell body. Source: Alzheimer’s news
What is a Lewy body?
A Lewy body is referred to as a cellular inclusion (that is, ‘a thing that is included within a whole’), 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) 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
How do Lewy bodies form? And what is their function?
The short answer to these questions is:
The longer answer is: Our understanding of how Lewy bodies are formed – and their actual role in neurodegenerative conditions like Parkinson’s – is extremely limited. No one has ever observed one forming. Lewy bodies are very difficult to generate in the lab under experimental conditions. And as for their function, this is the source of much guess work and serious debate (we’ll come back to this topic later in this post).
Ok, but what are Lewy bodies actually made of?
Mitochondrial division inhibitor-1 (mdivi-1) is a small molecule drug that is demonstrating very impressive effects in preclinical models of Parkinson’s disease. With further research it could represent a potential future therapy for people with Parkinson’s disease, particularly those with genetic mutations affecting the mitochondria in their cells.
What are mitochondria?
In this post, we will explain what mitochondria are, how they may be involved in Parkinson’s disease, and we will discuss what the results of new research mean for future therapeutic strategies.
Mitochondria are fascinating.
Utterly. Utterly. Fascinating.
On the most basic level, Mitochondria (mitochondrion, singular; from the Greek words mitos (thread) and chondros (granule)) are just tiny little bean-shaped structures within the cells in our body, and their primary function is to act as the power stations. They supply the bulk of energy that cells require to keep the lights on. This chemical form of energy produced by the mitochondria is called adenosine triphosphate (or ATP). Lots of mitochondria are required in each cell to help keep the cell alive (as is shown in the image below, which is showing just the mitochondria (red) and the nucleus (blue) of several cells).
Lots of mitochondria (red) inside cells (nucleus in blue). Source: Clonetech
That’s the basic stuff – the general definition you will find in most text books on biology.
But let me ask you this:
How on earth did mitochondria come to be inside each cell and playing such a fundamental role?
I don’t know. Are you going to tell me?
Because we simply don’t know.
But understand this: Mitochondria are intruders.
In this post we discuss several recently published research reports suggesting that Parkinson’s disease may be an autoimmune condition. “Autoimmunity” occurs when the defence system of the body starts attacks the body itself.
This new research does not explain what causes of Parkinson’s disease, but it could explain why certain brain cells are being lost in some people with Parkinson’s disease. And such information could point us towards novel therapeutic strategies.
The first issue of Nature. Source: SimpleWikipedia
The journal Nature was first published on 4th November 1869, by Alexander MacMillan. It hoped to “provide cultivated readers with an accessible forum for reading about advances in scientific knowledge.” It has subsequently become one of the most prestigious scientific journals in the world, with an online readership of approximately 3 million unique readers per month (almost as much as we have here at the SoPD).
Each Wednesday afternoon, researchers around the world await the weekly outpouring of new research from Nature. And this week a research report was published in Nature that could be big for the world of Parkinson’s disease. Really big!
On the 21st June, this report was published:
Title: T cells from patients with Parkinson’s disease recognize α-synuclein peptides
Authors: Sulzer D, Alcalay RN, Garretti F, Cote L, Kanter E, Agin-Liebes J, Liong C, McMurtrey C, Hildebrand WH, Mao X, Dawson VL, Dawson TM, Oseroff C, Pham J, Sidney J, Dillon MB, Carpenter C, Weiskopf D, Phillips E, Mallal S, Peters B, Frazier A, Lindestam Arlehamn CS, Sette A
Journal: Nature. 2017 Jun 21. doi: 10.1038/nature22815.
In their study, the investigators collected blood samples from 67 people with Parkinson’s disease and from 36 healthy patients (which were used as control samples). They then exposed the blood samples to fragments of proteins found in brain cells, including fragments of alpha synuclein – this is the protein that is so closely associated with Parkinson’s disease (it makes regular appearances on this blog).
What happened next was rather startling: the blood from the Parkinson’s patients had a strong reaction to two specific fragments of alpha synuclein, while the blood from the control subjects hardly reacted at all to these fragments.
In the image below, you will see the fragments listed along the bottom of the graph (protein fragments are labelled with combinations of alphabetical letters). The grey band on the plot indicates the two fragments that elicited a strong reaction from the blood cells – note the number of black dots (indicating PD samples) within the band, compared to the number of white dots (control samples). The numbers on the left side of the graph indicate the number of reacting cells per 100,000 blood cells.
The investigators concluded from this experiment that these alpha synuclein fragments may be acting as antigenic epitopes, which would drive immune responses in people with Parkinson’s disease and they decided to investigate this further.
The word ‘Kainos‘ comes from ancient Greek, meaning ‘new’ or ‘fresh’.
A company in South Korea has chosen to use this word as their name.
In today’s post we will discuss a clinical trial that started this week that is taking a ‘new and fresh’ approach to treating Parkinson’s disease.
Enchanting country. Source: Eoasia
South Korea is an amazing place, with a long and proud history of innovation and technological development. This week a biotech company there called Kainos Medicine has added itself to that history by initiating a clinical trial that takes a new approach to treating Parkinson’s disease.
As Kainos Medicine points out on their website, the current treatment options for Parkinson’s disease function by alleviating symptoms, for example L-dopa simply replaces the lost dopamine rather than treating the underlying disease. Kainos’s new experimental treatment, called KM-819, is trying to help in a different way: it is trying to slow down the cell death that is associated with Parkinson’s.
How does it do that?
KM-819 is an inhibitor of Fas Associated Factor 1 (or FAF1).
And what is FAF1?
Fas Associated Factor 1 is a protein that interacts with and enhances the activity of a protein on the surface of cells with the ominous name: Fas Cell Surface Death Receptor…and yes, the use of the word ‘death’ in that name should give you some indication as to the function of this protein. When Fas Cell Surface Death Receptor gets activated on any given cell, things have definitely taken a turn for the worse for that particular cell.
Fas Cell Surface Death Receptor (also called CD95) is an initiator of apoptosis.
What is apoptosis?
Apoptosis (from Ancient Greek for “falling off”) is the process of programmed cell death – a cell initiates a sequence of events that result in the cell shutting down and dying.
The process of apoptosis. Source: Abnova
Apoptosis is a very clean and organise process of a cell being removed from the body, with it eventually being broken down into small units (called apoptotic bodies) which are consumed by other cells.
Sounds interesting, but what research has been done on FAF1 and Parkinson’s disease?
Back in 2008, this research report was published:
Title: Fas-associated factor 1 and Parkinson’s disease.
Authors: Betarbet R, Anderson LR, Gearing M, Hodges TR, Fritz JJ, Lah JJ, Levey AI.
Journal: Neurobiol Dis. 2008 Sep;31(3):309-15.
PMID: 18573343 (This article is OPEN ACCESS if you would like to read it)
The researcher who conducted this study noticed that the FAF1 gene was located in the ‘PARK 10’ region of chromosome 1. PARK regions are areas of our DNA where mutations (or disruptions to the sequence of DNA) can result in increased vulnerability to Parkinson’s disease (there are currently at least 20 PARK regions). PARK 10 is a region of DNA in which mutations have been associated with late-onset Parkinson’s disease. The scientists thought this was interesting and investigated FAF1 in the context of Parkinson’s disease.
When they looked at postmortem brains, the researchers found that FAF1 levels were significantly increased in brains from people with Parkinson’s disease when compared to brains from healthy control cases. In addition, increased levels of FAF1 exaggerated the cell death observed in different cell culture models of Parkinson’s disease, suggesting an important role for FAF1 in sporadic Parkinson’s disease.
NOTE: More recently, a closer analysis of the PARK10 region resulted in a shrinking of the area which resulted in FAF1 falling outside the PARK10 domain (click here and here to see that research). We are currently not sure if genetic variations in the FAF1 gene infer vulnerability to PD.
This initial work led others to researching FAF1 in the context of Parkinson’s disease and in 2013 this research report was published:
Title: Accumulation of the parkin substrate, FAF1, plays a key role in the dopaminergic neurodegeneration.
Authors: Sul JW, Park MY, Shin J, Kim YR, Yoo SE, Kong YY, Kwon KS, Lee YH, Kim E.
Journal: Hum Mol Genet. 2013 Apr 15;22(8):1558-73.
These researchers found that Parkinson’s associated protein, Parkin (which we have briefly discussed in a previous post) labels FAF1 for disposal. And they found in the absence of Parkin there was a build up of FAF1, making the cells more vulnerable to apoptosis. They followed this finding up by demonstrating that FAF1-mediated cell death was rescued by re-introducing the normal parkin protein. Interestingly, there was no rescue when the mutant parkin protein was re-introduced. These results suggest that normal Parkin acts as an inhibitor FAF1.
To further investigate this finding, the researchers next modelled Parkinson’s disease in genetically engineered mice which had the FAF1 gene removed. They found that the behaviour motor problems and loss of dopamine cells in the brain was significantly reduced in the FAF1 mutant mice, indicating that the FAF1 pathway could be a worthy target for future Parkinson’s disease treatment.
And this and other research has led those same researchers to the clinical trial started in Korea by Kainos Medicine.
So what is the clinical trial all about?
The company will be conducting a phase 1 dose-escalation clinical trial in South Korea, which will evaluate the safety, tolerability, and biochemical properties of their drug KM-819 in 48 healthy adults (click here to read more about the trial).
This is the very first step in the clinical trial process.
The study is split in two parts: Part A is a single dose of KM-819 or a placebo given in ascending doses to participants. And Part B is the same except that multiple ascending doses of the compound will be given to the participants.
The trial will last around six weeks, and – according to the press release – the first subject has just been dosed.
What does it all mean?
Parkinson’s disease is a neurodegenerative condition, which means that certain cells in the brain are dying. Medication that could block that cell death from occurring represents an interesting way of treating the disease and this is what Kainos are attempting to do.
Blocking or slowing cell death is a tricky business, however, because in other parts of the body, cell death is a very necessary biological process. In some areas of our body, cells are born, conduct a particular function and die off relatively quickly. By slowing that cell death in the brain which may be a good thing, we may be causing issues elsewhere in the body, which would be bad.
In addition there has recently been concerns raised about the clinical use of apoptosis inhibitors, such as this study:
Title: Caspase Inhibition Prevents Tumor Necrosis Factor-α-Induced Apoptosis and Promotes Necrotic CellDeath in Mouse Hepatocytes in Vivo and in Vitro.
Authors: Ni HM, McGill MR, Chao X, Woolbright BL, Jaeschke H, Ding WX.
Journal: Am J Pathol. 2016 Oct;186(10):2623-36.
The researchers who conducted this study found that using apoptosis inhibitors on a mouse model of liver disease did stop apoptosis from occurring, but this didn’t save the cells which eventually died via another cell death mechanism called necrosis (from the Greek meaning “death, the act of killing” – lots of Greek in this post!). In necrosis, rather than breaking down in a systematic and organised fashion (apoptosis), a cell will simply rupture and fall apart. Very messy.
Thus there is the possibility with the Kainos drug, KM-819, will protect cells in the Parkinsonian brain from dying via apoptosis, but as the disease continues to progress those cells may become more ill and eventually disappear as a result of necrosis. That said, if the drug can slow down Parkinson’s disease, it would still represent a major step forward in our treatment of the condition!
The connection with Parkin is also very interesting.
It would be wise for future phase 2 and 3 trials – which will test efficacy – to include (or specifically recruit) people with Parkinson’s disease who have mutations in the Parkin gene. This is a very small proportion of the overall Parkinson’s community (approx. 20% of people with early onset PD have a Parkin mutation – click here to read more on this), but if the drug is going to be effective, these would be the best people to initially test it in.
This will be a very interesting set of clinical trials to watch. The phase 1 safety trial will be very quick (6 weeks), and hopefully Kainos Medicine will be able to progress rapidly to a phase 2 efficacy trial. Fingers crossed for positive results.
The banner for today’s post was sourced from Koreabizwire