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“Precision medicine” is an emerging model of therapeutic intervention in which treatment options are tailored to a specific subtype of a condition or even on an individual patient-based metric that involves an intergrated analysis of his/her comprehensive “-omics” data.
Many different methods of stratifying patients have been proposed and many of them involve adding the word “-omics” to the end of their labels. But these efforts may start to pay big dividends in clinical trials exploring potentially disease modifying therapies in the not too distant future, including in the case of Parkinson’s.
In today’s post, we will look at one such clinical study exploring better patient stratification in Parkinson’s.
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The original “Make America Great Again”. Source: NYTimes
I think it all started with Ronald Regan.
But I’m not really too sure.
Or more specifically, not Reagan himself, but rather the 1980s conservative radio broadcaster Paul Harvey.
Paul Harvey. Source: Youtube
You see, Harvey was the person who apparently came up with the portmanteau “Reaganomics“. People liked the play on words and thought that it was a clever little label to explain a rather complex subject. But the name kicked off a barrage of imitators with every man and his dog coming up with their own version of -omics.
And scientists really got carried away with the adoption of different kinds of -omics. Every field of research it seems has continuously been inventing new “-omics”. There’s even a wikipedia page for all the different kinds of -omics, and their use has changed our speecheomics (and yes, that really is an actual word).
I am used your posts having odd starting points, but where exactly is this intro going?
Well, I needed to introduce that idea of “-omics” in order for the rest of this post to work.
Oh I see. So what do we mean by -omics?
Humans love grouping things. It makes stuff easier to think about.
And this applies to the biological sciences as well, where the activities of complex systems (such as our genomes – the entirety of our DNA) are easier to discuss at a high level by giving them a simple label (in this case: genomics).
Such terms are useful and have become widely adopted by research scientists
“Omics” basically refer to the collective characterization and quantification of pools of biological data. So the experiments focused on collecting and analysing cell metabolism data is often referred to as metabolomics. Other common types of -omics are ‘proteomics‘ (examination of proteins) and ‘transcriptomics’ (study of RNA molecules).
And there is even collective pronouns for situations involving more than one -omics: ‘Trans-omics‘.
Lot of different potential -omics. Source: Wikipedia
Labels aside, the data being collected and analysed within these disciplines could be extremely useful in helping us to better stratify participants in clinical trials for new therapies to treat Parkinson’s.
What do you mean?
At present, a lot of clinical trials involve testing a new drug on a group of people with Parkinson’s. The inclusion criteria for these trials is often very broad: The participant must be 30-80 years of age, diagnosed with PD, not cognitively impaired,… etc.
But as we have discussed on this website, the variability between people with Parkinson’s is significant. Some are more tremor-dominant, while others have rigidity issues. Some people with Parkinson’s progress very rapidly, while others have a much slower course.
So the question is: Should all of these people with a diagnosis of “Parkinson’s” be expected to respond the same way to an experimental new treatment?
Maybe they will, maybe they won’t – it really depends on the treatment being tested.
But to provide a higher chance of success, we could try targeting the new treatment towards a specific group of people with Parkinson’s who have the highest chance of responding to it.
Can you give an example of this?
Yes, there is a class of drugs called LRRK2 inhibitors that are being developed for Parkinson’s (Click here to read a previous post about this). The first of these agents to be tested to being targeted at individuals who carry a genetic variant that causes their LRRK2 protein to be hyperactive.
LRRK2 protein. Source: Youtube
Rather than testing LRRK2 inhibitors in everyone with Parkinson’s, the researchers who are developing these agents are first testing it in the group of PD patients who most likely to benefit the most from it. And they are using “genomics” to identify these individuals – by sequencing their DNA to determine if they have a genetic variation in their LRRK2 gene.
I see. How else might this omics stuff be used?
Well, there is a clinical trial in Germany at the moment that is employing -omics to test an old drug in a more carefully defined cohort of people with Parkinson’s.
This report provides the overview and rationale behind the study:
Title: An omics-based strategy using coenzyme Q10 in patients with Parkinson’s disease: concept evaluation in a double-blind randomized placebo-controlled parallel group trial.
Authors: Prasuhn J, Brüggemann N, Hessler N, Berg D, Gasser T, Brockmann K, Olbrich D, Ziegler A, König IR, Klein C, Kasten M.
Journal: Neurol Res Pract. 2019 Aug 23;1:31.
PMID: 33324897 (This report is OPEN ACCESS if you would like to read it)
In this study, the researchers are seeking to focus on a very specifically defined sub-group of the wider Parkinson’s affected population, with a goal of disease modification. They want to specifically treat individuals with genetic variants associated with mitochondrial function.
Remind me again: What does mitochondrial function refer to?
Mitochondria are tiny bean shaped objects that reside inside of almost every cell in your body.
Mitochondria. Source: Ohiostate
They function as the power stations of each cell and there are hundreds (often thousands) of them per cell, being moved around internally as needs dictate.
Disturbances of mitochondrial function have been shown to occur in individuals with Parkinson’s who carry genetic mutations in the genes Parkin and PINK1 (Click here to read a previous SOPD post about these genes). And for this reason, the researchers are focusing all of their attention in this clinical trial on testing an agent that will improve mitochondrial function in individuals with PINK1 or Parkin-associated Parkinson’s (Click here to learn more about Parkin-associated PD).
To do this, the researchers have set up a double-blind, randomized, placebo-controlled clinical trial, in which they will treat these individuals with the “mitochondrial enhancer” Coenzyme Q10 (156mg of QuinoMit Q10 fluid per day) for 6 months.
What is Coenzyme Q10?
First isolated from beef heart mitochondria by Dr. Frederick Crane (Wisconsin, USA) in 1957, Coenzyme Q10 (also known as ubiquinone-10) is a co-enzyme that is ubiquitous throughout the animal kingdom.
The “Q” refers to the quinone chemical group involved and the “10” refers to the number of isoprenyl chemical subunits in its tail:
Coenzyme Q10 structure. Source: Chemodex
Coenzyme Q10 is an antioxidant that your body produces naturally. It is very good at dealing with oxidative stress.
What is oxidative stress?
Oxidation involves the loss of electrons from a molecule, which in turn destabilises that particular molecule.
Think of iron rusting.
Rust is simply the oxidation of iron – in the presence of oxygen and water, iron molecules will lose electrons over time. Given enough time, this results in the complete break down of objects made of iron.
Rusting iron. Source: Thoughtco
The exact same process occurs in biology. Molecules in your body go through a similar process of oxidation – losing electrons and becoming unstable. This chemical reaction leads to the production of what we call free radicals.
What are free radicals?
A free radical is an atom, molecule, or ion that has at least one unpaired electron. In effect, it is an extremely unstable entity.
Due to the lack of a stable number of electrons, free radicals are in a constant state of searching for another electron to help stabilise themselves. This chaotic activity of these unstable atoms can result in damage to cells – particularly the all-important DNA – and can ultimately lead to cell death.
What can cause the production of free radicals?
Lots of things.
They can be produced naturally in the body as a by-product of metabolism, or by exposure to environmental toxins such as tobacco smoke or ultraviolet light.
One very common type of free radicals are reactive oxygen species.
What are reactive oxygen species?
Reactive oxygen species (or ROS) is an umbrella term for an large array of derivatives of molecular oxygen that occur through the normal cellular functioning of cells. When oxygen (O2) loses an electron, it results in “superoxide”.
And just because superoxide has the word ‘super’ in it, does not mean that it is one of the good guys. Superoxide is the precursor to most other ROS.
The generation of ROS inside of cells largely occurs in the mitochondria – which we were talking about further up in this post:
A mitochondrion (singular) and its location in the cell. Source: NCBI
ROS often leak out of a structure inside of mitochondria called the electron transport chain. It is located on the inner wall of the mitochondrial membrane.
What is the electron transport chain?
The electron transport chain is a series of protein complexes that produces adenosine triphosphate (or ATP), which is the energy-carrying molecule found in the cells of all living things. ATP provides energy to drive many processes in living cells.
An explanation of the electron transport chain requires an entire website of its own. This video, however, does an excellent good job of providing an overview:
The electron transport chain is amazing, but it is not a perfect system. And its activities result in the production of ROS, which can leak out of the mitochondria and cause trouble in cells.
Because mitochondria produce so many ROS from their continual production of energy, our cells have developed an assortment of defense systems to clean up ROS and maintain a stable environment.
One common defense is the production of antioxidants.
What is an antioxidant?
While free radicals are the bad guys in oxidation, antioxidants can be considered the good guys. They are molecules that neutralize the free radicals by donating one of their own electrons. The antioxidant do not become free radicals by donating an electron because by their very nature they are stable with or without that extra electron.
How free radicals and antioxidants work. Source: h2miraclewater
Coenzyme Q10 is an essential cofactor of the electron transport chain as well as a potent free radical scavenger in lipid and mitochondrial membranes
So if Coenzyme Q10 is naturally produced, what happens to it in people with Parkinson’s?
Recently there has a review of the data on this question (Click here to read that report). The researchers pooled all of the available data from multiple studies and they found that “compared with controls, Parkinson’s patients have decreased Coenzyme Q10 levels in the cerebellar cortex, platelets, and lymphocytes, increased total and oxidized Coenzyme Q10 levels in the cerebrospinal fluid” (“oxidized Coenzyme Q10” means that the molecule is no longer an antioxidant – it has done its job. It is spent).
In addition to this, there is a lot of preclinical data demonstrating that Coenzyme Q10 is neuroprotective in models of neurodegeneration. For example:
Title: Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects.
Authors: Matthews RT, Yang L, Browne S, Baik M, Beal MF.
Journal: Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8892-7.
PMID: 9671775 (This report is OPEN ACCESS if you would like to read it)
In this study, the researchers examined the effects of Coenzyme Q10 on survival in a genetic animal models of amyotrophic lateral sclerosis (ALS, also known as motor neuron disease) and Huntington’s disease, and found that it increased mitochondrial concentrations in the brain and produces neuroprotective effects in both models.
And similar results have been observed in preclinical models of Parkinson’s (Click here to read more about this).
Interesting. Has Coenzyme Q10 ever been tested in a Parkinson’s clinical trial before?
Yes it has.
Between May 1999 and February 2000, 80 individuals recently diagnosed with Parkinson’s were recruited to this study:
Title: Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline.
Authors: Shults CW, Oakes D, Kieburtz K, Beal MF, Haas R, Plumb S, Juncos JL, Nutt J, Shoulson I, Carter J, Kompoliti K, Perlmutter JS, Reich S, Stern M, Watts RL, Kurlan R, Molho E, Harrison M, Lew M; Parkinson Study Group.
Journal: Arch Neurol. 2002 Oct;59(10):1541-50. d
PMID: 12374491 (This report is OPEN ACCESS if you would like to read it)
In this study, the researchers randomly assigned the 80 participants to one of four treatment groups (300-, 600-, or 1200-mg/day of Coenzyme Q10, or placebo). The participants were followed and evaluated for up to 16 months or until they required the initiation of levodopa treatment.
The results indicated that Coenzyme Q10 was safe and well tolerated even at the highest dose used in the study (1200 mg/day). But most intriguingly, the 1200-mg/day dose was associated with a significant slowing of the progression of Parkinson’s symptoms (as measured by the total UPDRS score – the greatest benefit was observed in Part II, activities of daily living). Even the lower doses of Coenzyme Q10 resulted in better outcomes than the placebo treated group.
This result were obviously very encouraging, but the study was too small (only 20 participants in each treatment group) to make any serious conclusions, so the investigators initiated a larger Phase III randomized, placebo-controlled, double-blind clinical trial.
This was the report from that second study:
Title: A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit.
Authors: Parkinson Study Group QE3 Investigators
Journal: JAMA Neurol. 2014 May;71(5):543-52.
PMID: 24664227 (This report is OPEN ACCESS if you would like to read it)
This study took place across 67 North American research sites and involved 600 participants who were randomly assigned to receive either placebo, 1200 mg/day of Coenzyme Q10, or 2400 mg/day of Coenzyme Q10. All participants in the study also received 1200 IU/day of vitamin E (The vitamin E was used in combination with Coenzyme Q10 because it had been reported that together with Coenzyme Q10 it may have a synergistic antioxidant effect, plus it also enhances Coenzyme Q10 absorption) (Click here to read more about the details of the study).
Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit.
At the end of the study when the results were analysed, Coenzyme Q10 was found to be safe and well tolerated, but it showed no evidence of clinical benefit. As you can see in the graph below, there was no difference between the three treated groups – they all increased in their UPDRS score by approximately the same amount, suggesting that the progression of symptoms was the same across all three groups:
How did they explain the difference between the results of the two studies?
In their report, the investigators wrote “the participants were demographically and clinically similar to those in the Coenzyme Q10 Phase 2 study. There were no major imbalances between treatment groups regarding baseline variables, premature withdrawals, serious adverse events, or other study incidents that could explain the different results for the 2 studies”. And as a result of this result, the researchers could not “recommend Coenzyme Q10 for the treatment of early Parkinson’s”.
And unfortunately another randomized, double-blind, placebo-controlled 12-month study investigating a Coenzyme Q10 derivative, called MitoQ, had also failed to demonstrate any benefit in a 128 individuals with recently diagnosed Parkinson’s shortly before the Phase 3 trial results were announced (Click here to read more about this study).
Ok, so why are the -omics researchers now re-testing this Coenzyme Q10 agent?
Well, as we discussed above, a molecule like Coenzyme Q10 is best targeted at a population of people with Parkinson’s that is associated with mitochondrial function issues, rather than just anyone with “Parkinson’s”.
So the researchers in Germany will be using ‘genomics‘ to identify participants for their study who carry very specific genetic risk factors associated with mitochondrial function.
I see. What does the new study involve?
The study will involve testing Coenzyme Q10 (or a placebo) in people with multiple (homozygote) Parkin/PINK1 mutations or single (heterozygote) Parkin/PINK1 mutation carriers. The researchers will also be recruiting individuals with Parkinson’s who a very specific genetic variant in one of eight potential locations in their DNA. These individuals are considered the “omics” groups, and an “omics” negative group of Parkinson’s patients will also be recruited and used as a control group. In total there will be 72 participants in total, and the study will be performed in a double-blind, randomized, and placebo-controlled parallel group fashion – as described in this schematic:
The study will involve 6 months of Coenzyme Q10 or a placebo treatment for the participants, and the primary endpoint will be the change in motor symptoms compared to baseline measures (as determined by the MDS-UPDRS part III). Additional endpoints will include non-motor symptoms and brain imaging results (31P-magnetic resonance spectroscopy imaging and MRI). After the 6 months of treatment, there will be a 3 month follow up period (Click here to read more about the details of this study).
It will be really interesting to see the results of this specifically targeted -omics study when they become available. The study was first registered in 2018, but I am assuming that COVID19 will have slowed progress.
So what does it all mean?
I need to correct something I said above: Paul Harvey and Regan had nothing to do with it.
The first -omics word was genomics and it was first coined by a geneticist at the Jackson Laboratory named Dr. Thomas Roderick at a place called McDonald’s Raw Bar in 1986 (source). And the term ‘economics‘ is unrelated to the use of ‘-omics’ here (see Wikipedia for more on this). My apologies for any misunderstandings.
Better patient stratification using various -omic approaches is hopefully the future of Parkinson’s research. It will allow for more accurate testing of therapeutic agents targeting specific pathways associated with some of the biology potentially underlying some forms of the condition we know of as “Parkinson’s”. Further -omics investigations of the “Parkinson’s” cohorts will also provide us with a deeper understanding of the biology associated, which will ideally lead to new and more potent treatments.
High expectations? Perhaps. But these methods will certainly generate a lot of new data.
And as I say, we here at SoPD HQ will be looking out for the results of the current -omics clinical trial on Coenzyme Q10.
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