Meet the Researcher: Professor Huw Morris on developing the role of genetics in Parkinson’s clinical trials

In this series from Cure Parkinson’s, we hear directly from the scientists putting our funded research projects into action. From learning about their career journeys to getting an inside look at their studies, we’ll discover how their work aims to support people living with Parkinson’s.  

In this Meet the Researcher interview, Professor Huw Morris, a neurologist based in London, discusses his career studying genetics, the importance of combining clinical and genetic data when exploring Parkinson’s and why identifying genetic causes of the condition is crucial to developing future therapies and drugs to target the condition.

How do genetics interact with the progression of Parkinson’s?

This question has been at the core of Professor Huw Morris’s career. As a Professor of Neurology and Neurogenetics at University College London (UCL), his work aims to use genetic information to help develop new treatments for people living with Parkinson’s.

“A lot of time has been spent over the last 30 years studying Parkinson’s genetics – trying to understand more about the biology of the condition, why it happens and exploring what the genetic risk factors are that lead to the condition,” Huw says. “And while that is really interesting scientifically and biologically, it’s completely meaningless unless it’s transferred into new treatments for patients. That’s where we really need to focus.”

There are several genetic variations that are associated with an increased risk of Parkinson’s. Genes are sections of our DNA (genetic material) that help direct cell activity by providing the instructions for building proteins. Small changes in these genes can impact how well its associated protein functions, sometimes leading to larger issues in the cell. For example, variation in the GBA-1 gene, the most common genetic risk factor for Parkinson’s, affects the cell’s waste disposal system.

Huw and his team at UCL are particularly interested in understanding how genetics may affect the progression of people’s Parkinson’s symptoms.

“Sometimes when we see patients, they have very minimal symptoms and they’re very active and independent 20 years after the onset of their condition, but other people are developing numerous problems within two or three years of their diagnosis. So, there’s a huge variation in people living with Parkinson’s between how they progress and how their symptoms change over time,” he explains. “If we understood what the basis of that was, that would be really good in helping us to develop a disease-modifying treatment to stop Parkinson’s getting worse over time.” 

So, what’s key to achieving this? Data, he says. “At the core of human genetics research is having really good clinical data on the type of problems people with Parkinson’s have and linking this with their genetic variation (observable traits and family history).” As well as helping us understand why there is variation in Parkinson’s progression, genetic information may help us to understand the outcomes of clinical trials.

Marrying up clinical and genetic data

This is where Huw and his team at UCL come in. With grant funding from Cure Parkinson’s since 2016, they collected 2782 samples from people living with Parkinson’s who had participated in UK clinical trials.

These samples were genetically sequenced and then stored in a biobank for the investigators on participating trials to use for analyses. Many of the trials included in this biobank involve drugs that were evaluated by Cure Parkinson’s International Linked Clinical Trials (iLCT) committee, such as simvastatin and exenatide.

Through this project, they’re aiming to marry up this clinical data with genetic data to advance our understanding of how genetic risk factors impact Parkinson’s progression and responses to treatment, as well as establishing an open access resource for researchers to use.

“Ultimately, the aim is that we’ll be able to look back at clinical trials and work out why some people might respond to a therapy and why some do not,” Huw says. “We think at some level this might be determined by your genetic makeup. So, the way to take that forward is to collect genetic samples from patients who consent to this in clinical trials.”

The project had three main goals, Huw outlines. “The first was to establish the feasibility of whether patients in clinical trials will consent to donating samples for genetic research,” he explains. He estimates that around 80% of the people they asked were happy to consent to donate a sample. 

The second part of the project, Huw says, “is trying to answer the question: are there some subgroups of Parkinson’s patients who respond well to treatment? And then lastly, the third goal is trying to use this data to understand the biology of the progression of Parkinson’s.” 

Creating a global initiative

In addition to the Cure Parkinson’s biobank, they have also submitted this data to the Global Parkinson’s Genetic Program (GP2). GP2 is an initiative that collects genetic data from Parkinson’s trials around the world to help researchers better understand the genetic architecture of Parkinson’s. GP2 is a resource program of Aligning Science Across Parkinson’s (ASAP), managed by the Coalition for Aligning Science and implemented by the Michael J. Fox Foundation. 

“We have about 20 drug trials where we have generated genetic data linked to clinical trial data,” Huw says. However, he notes that most of the trials involved are academic, rather than industry-led – an area he feels there’s potential for more collaboration. “This is a really important place where Cure Parkinson’s can help us, through liaising with industry to encourage them to share their data. I think that really will help to drive the field forward, and hopefully help us to develop new drug targets,” he adds. “We need to make sure that trials are getting the maximum benefit for patients, particularly if they’re unsuccessful – and that we use the data from trials and the samples collected to help develop the next one.”

Something that his work with GP2 has highlighted is the need for diversity in genetic research. “Most of this research has been done on white European people in North America and Europe. There is a massive underrepresentation in terms of the world’s population in our understanding of genetics.”

Huw says this needs to change in order to improve equity in the research field. “If we’re going to develop new treatments, it’s really important that those treatments work and are applicable to people, whatever part of the world they’re from.”

These insights are also valuable from a biological perspective, he points out. “These slight differences in genetic backgrounds enable you to get much more information when you compare people with Parkinson’s from Africa, South Asia, East Asia and Northern Europe with Parkinson’s. Putting the data together could give you much more insight into what’s going on with the development of the condition.” This is a key area that GP2 is trying to develop, with a third of its data having so far been generated from non-European populations. 

Exploring familial links

Huw has witnessed first-hand how rapidly our understanding of genetics has advanced. 

His PhD at UCL focused on the genetics of progressive supranuclear palsy (PSP), a rare neurological condition that can cause problems with balance, movement, vision, speech, and swallowing. Part of this involved Huw travelling to Guam, an island in the western Pacific, to study Parkinsonism-dementia complex – a rare, progressive neurodegenerative condition only found on the island.

“In the 1990’s, Parkinson’s was thought to be almost entirely caused by environmental factors,” he explains. “Many people said there were no genetic factors in Parkinson’s.”

However, since then, a number of genetic variations have been found that increase the risk of Parkinson’s. “Currently, there are about 140 places across the genome where there are variations across a number of genes that increase the risk of Parkinson’s,” Huw says. “This has been a progressive effort over the last 30 years.”

Another core part of Huw’s work at UCL is being the lead researcher on the Parkinson’s Family Project, which runs across the UK. They aim to connect with people living with early onset Parkinson’s or people who have a family history of the condition, to see if there are any genetic links. “We’re really interested in making contact with these families,” Huw says. While he acknowledges that it’s unusual to have families where multiple members are affected by Parkinson’s, it’s these rare families that have previously led to major insights into the biology of the condition. Huw cites the gene associated with alpha-synuclein as an example, as well as the variations in the LRRK2 gene.

“There are trials running now which are directed towards these drug targets, which have really come from genetics,” he says. “Currently, having a genetic risk factor does not change your Parkinson’s treatment. But we hope that in the future, there will be a drug or therapy that can target these variants, helping to prevent Parkinson’s progression in individuals with those risk factors. Identifying these genetic causes is very exciting for developing future drugs and therapies.”

It’s evident from Huw’s work that the genetics of Parkinson’s is an area of research that shows no signs of slowing down anytime soon and may eventually play a role in how we diagnose and treat Parkinson’s.