Precision medicine for Parkinson’s, how close are we?
As we inch ever closer to identifying subtypes and the promise of precision medicine, is the current one-size-fits-all approach to Parkinson’s set to change?
--
Today we treat Parkinson’s as one condition, but research is pointing towards the presence of different sub-types, which could turn treatment on its head. When it comes to sub-typing, we can learn a lot from other conditions and one in particular…
Lessons from cancer
One of the greatest and evolving success stories for treating subtypes of a condition comes from cancer.
For decades, the main options for treating cancer have been:
- chemotherapy which floods the body with toxic chemicals
- radiotherapy which uses damaging radiation
- or a combination of both
Chemo and radiation are both effective ways to kill cancerous cells but they are hard to target at cancerous cells alone. This means they can also do a lot of damage to healthy, non cancerous tissues and organs causing horrible side effects.
Better and more targeted ways to use chemo and radiotherapy have been developed and they are both still a vital part of cancer treatment — but the search was still on for something better.
Then researchers studying tumours from many different cancers noticed something crucial: not all cancers are equal. And instead of categorising and treating cancer based on where it appears in the body, targeting the biological features of the particular cancer could provide the key to better treatments. Cancers needed to be subtyped.
“One of the best ways to deal with cancer is to divide and conquer, based on as much knowledge as we can get of how individual tumours work. Treating all cancers from the same part of the body equally isn’t good enough — you must match the right patient with the right treatment.”
Read the full article in The Guardian
For example, we know now that high levels of a protein called HER2 are found in some types of breast, oesophageal and stomach cancer. This overactivity of HER2 helps the cancer cells grow and survive.
Understanding the role HER2 plays in these cancers led to the development of a new precision medicine— Trastuzumab (also known by its brand name Herceptin) — which works by specifically targeting and blocking the activity of HER2 and encouraging the immune system to attack and kill the cancer cells.
Trastuzumab is just one example of a new wave of precision medicines that zero in on a specific target in cancer cells and aim to leave healthy cells alone. While they’re not a magic bullet - they can still have severe side effects and many cancers are still waiting for them - targeted treatments are slowly but surely revolutionising the treatment of cancer.
So the question is, can we use the same approach to treat Parkinson’s?
Parkinson’s — how many subtypes are there?
We already know that there are different forms Parkinsonism - a term that covers a range of conditions that have similar movement symptoms including slowness, stiffness and tremor.
Most people with a form of parkinsonism have idiopathic Parkinson’s disease, also known as Parkinson’s. But other forms include vascular Parkinsonism, Multiple System Atrophy and Progressive Supranuclear Palsy.
All these conditions share similar symptoms but have quite different underlying biology. This means they usually don’t respond as well to the main treatment used for Parkinson’s: levodopa. Is levodopa then, the Parkinson’s equivalent of chemotherapy?
Now scientists are trying to work out whether it’s possible to break Parkinson’s itself down into smaller categories — or subtypes — that can help us treat the condition in a more targeted and personalised way.
Sorting Parkinson’s into subtypes
One approach for doing this is to use patterns in symptoms, response to treatment and progression to categorise people into subtypes.
To spot these patterns we need to study vast numbers of people with the condition over time, which is exactly what researchers in the UK have been doing in two Parkinson’s UK funded studies:
- Tracking Parkinson’s led by Professor Donald Grosset and launched in 2012 is a UK-wide study involving more than 2,000 people.
- The Discovery Study led by Dr Michele Hu launched as part of the Oxford Parkinson’s Disease Centre in 2010 and involves more than 1,000 people.
Together the two studies are collecting detailed information about the condition from thousands of participants with Parkinson’s who joined the studies soon after diagnosis.
In both, participants are assessed every 18 months using a range of different tests to take a detailed picture of their symptoms and track how the condition is developing.
Crucially, the two studies were designed collaboratively to ensure that they are collecting the same information so that they can be easily compared.
Recently, the two teams joined forces to analyse their data and used sophisticated data analysis to identify 4 possible subtypes (or ‘clusters’) of Parkinson’s - read the full paper describing their findings here.
The four clusters are based on peoples’ symptoms at their first study visit (see below diagram).
The analysis showed that the four clusters of people who shared similar symptoms at the start tended to progress in similar ways.
Those with symmetrical motor symptoms (meaning that they are equally affected on both sides of the body), poor sense of smell, low blood pressure, memory problems and respond poorly to levodopa were likely to experience faster worsening in their symptoms.
Whereas those who present with a prominent tremor on one side, have an average level of non-motor symptoms and also respond poorly to levodopa seemed to have the slowest progressing form of the condition.
Importantly, the clusters were consistent in both studies, which suggests that they may represent real subtypes of Parkinson’s.
Deputy Research Director at Parkinson’s UK, Dr David Dexter, comments:
“It’s still early days. We need to continue following these important participants for much longer to see whether the clusters the researchers have identified continue to hold true. We also need to see whether what they’ve found in our UK population holds true for people in other countries as well.
“What’s most exciting about identifying these clusters is the potential they may bring to provide the right treatments and support— whether that be drugs, exercise or other therapies — to suit the individuals and their form of the condition best.
“Crucially, both Tracking and Discovery studies have also been collecting blood samples for genetic and protein analysis, doing extensive brain scanning and encouraging people to sign up to the Parkinson’s UK Brain Bank to donate their brains.
“This means we have the opportunity to link up what we’re seeing in the symptoms and progression of the participants to what is happening at a biological level. It may be that different biological problems lie at the heart of the different subtypes and require different treatment approaches.”
New precision treatments are on the way
So if levodopa is the Parkinson’s equivalent of chemotherapy, where are the new targeted treatments like Trastuzumab going to come from?
An explosion in our understanding of the biological changes involved in the development of Parkinson’s means that new drugs designed to fix these problems are already well on the way. And some of the most advanced have arisen from our growing understanding of the host of different genetic changes involved in Parkinson’s.
The discovery of one of the most common genes known to be involved in Parkinson’s — LRRK2 — has led to the development of new drugs that are now being tested in clinical trials.
People who have a particular form of the LRRK2 gene called G2019S, have around a 70% chance of being diagnosed with Parkinson’s by the age of 80, and there are also a number of other different versions that also increase risk of developing the condition.
The LRRK2 gene provides the instructions for building the LRRK2 protein, which until it was first linked to Parkinson’s back in 2004, was just another anonymous protein floating around in our cells and we had simply no idea what it did or that it might be important in the condition.
Over a decade later, LRRK2 remains a bit of a mystery but research suggests that this large and complex protein is involved in a wide range of important activities inside cells which include:
- keeping mitochondria — the energy-producing batteries of the cell — healthy and working well
- processing waste inside cells
- the packaging, trafficking and release of neurotransmitters (like dopamine) from brain cells
The altered versions of LRRK2 linked to Parkinson’s make the protein overactive. This means finding ways to lower LRRK2 activity could be the key to new therapies.
Scientists have now been able to create intricately detailed 3D maps of the LRRK2 protein and use them to design tiny molecules that can attach to the overactive part of the protein and switch it off.
As a result of all this painstaking scientific work, there are now new drugs called LRRK2-inhibitors on their way. One of the most advanced of these, DNL201, has been developed by biotech company Denali Therapeutics and was recently tested in healthy subjects (without Parkinson’s) for the first time in a phase 1 clinical trial.
The results were reported by Denali in August 2018. Encouragingly, not only was the drug safe and well-tolerated but there were also positive signs that it successfully got into the brain and was doing it’s job when it got there — ie. reducing LRRK2 activity.
The next step for DNL201 is for it to be tested in people affected by Parkinson’s who carry an altered version of the LRRK2 gene and we expect to hear more about these further studies in 2019.
And while the inspiration for developing these new drugs originated with patients who carry a rare genetic mutation, recent research suggests that treatments that reduce LRRK2 activity could be beneficial for people with other forms of the condition too.
How subtypes could change the future
The ability to subtype Parkinson’s not only holds the power to transform the way we treat the condition in the future but also the way we test new treatments in the shorter term.
If we can nail down subtypes of Parkinson’s and understand their biology then in the future we may be able to use a simple test — like a blood test — to categorise people at the point of diagnosis.
Then based on their subtype of Parkinson’s, the aim is to provide the right combination of treatments and therapies to specifically address the symptoms and biological features of their condition.
But before we get there, subtyping could be the key to improving the way we test new treatments in clinical trials.
Currently in clinical trials everyone with Parkinson’s is included, so you have a mix of people who progress slowly and those who progress rapidly. Unsurprisingly, this often means that the results show a range of responses — with some people responding well to the new treatment and others poorly.
This inconsistency in how people with Parkinson’s respond to different treatments makes it very difficult to assess the ability of new drugs fairly. Is a drug useless or does it only work in certain subtypes of the condition?
Subtypes will enable trials to test the right treatments in the right people. This would give trials a better chance of successfully identifying treatments that are truly effective, and would massively accelerate the hunt for new and better treatments and ultimately a cure.
