Can precision medicine unlock the potential to halt the progression of Parkinson’s Disease?

Parkinson's Disease is a common brain disorder that currently affects around 145,000 people in the UK. Each day, 80 people in the UK are newly diagnosed with this condition. People are usually diagnosed with Parkinson’s because of their motor symptoms, which include tremor, problems with walking and coordination. However, it can also cause many other symptoms such as depression and anxiety or marked constipation.

Oliver Bandmann, Professor of Movement Disorders Neurology, NIHR Sheffield BRC Investigator and Honorary Consultant Neurologist at Sheffield Teaching Hospitals NHS Foundation Trust, and his team recognise Parkinson’s Disease as a global problem that must be addressed. “Every patient differs from the next with their symptoms and we don’t know why. We also don’t know why some patients progress quickly and others only slowly or why some patients respond well to medication and others don’t. The number of people with Parkinson’s worldwide is predicted to double between 2007 and 2030 – we urgently need to gain a better understanding of the disease. Research on Parkinson’s is needed more urgently than ever – in the US alone, the annual costs arising from Parkinson’s exceed $50 Billion Dollars! Any money spent on research today can reduce both costs and suffering later.”

Dr Heather Mortiboys, Senior Lecturer in Translational Neuroscience and Parkinson's UK Senior Research Fellow, explains “We don’t yet fully understand why brain cells are dying in Parkinson’s. The reasons are almost certainly not the same in every patient; presenting even more of a challenge for us. Added to this we cannot take brain biopsies of patients so we need a model in which we can study these mechanisms.”

Pam Irvine is a patient of Professor Bandmann's and was diagnosed with Parkinson’s Disease in 2017. “There are some things that had been so hard, and before I saw Professor Bandmann I had difficulty getting out of bed. I couldn’t dress myself very well, Mike (my husband) had to cut my food up for me, I’d lost my swallowing reflex, I had bladder problems - the list was endless.” 

Professor Bandmann explains “At the beginning of the disease, some symptoms respond well to medication. However, the longer a patient has the disease, the less well the drugs work and the more likely patients are to develop side effects. There isn’t currently a treatment that will slow the progression of the disease and we don’t have a means to influence how a patient responds.” 

But scientists and clinicians at the University of Sheffield are working with patients to change this. By gaining a better understanding of the disease they are working towards new and potentially life-changing treatments to slow it down and one day halt it in its tracks.

Using advanced science to screen potential treatments

Parkinson’s patients in Sheffield and London are taking part in a clinical trial led by NIHR Sheffield Biomedical Research Centre to test a drug, for the first time, which could slow progression of the disease.

Every brain cell contains chemicals which are used to communicate with other brain cells - this is fundamental to their function. The brain cells particularly affected in Parkinson's contain the chemical dopamine which are vital for healthy coordination and movement. They rely on energy-producing mitochondria to function, but in people living with Parkinson’s the mitochondria, or ‘powerhouse’ of the cells, are disrupted and the cells begin to fail and slowly die.

Between 2009 and 2013 the Sheffield Parkinson’s disease research team at the Sheffield Institute for Translational Neuroscience (SITraN) completed the world’s first drug screen in Parkinson’s patient tissue. After assessing over 2,000 drugs, they have identified a number which could boost the function of dopamine-containing brain cells.

The team identified a potential drug that has already been in use for decades to treat liver disease. Ursodeoxycholic acid (UDCA) demonstrated beneficial effects on the patient tissue and was found to improve mitochondrial function. Using fly models with Parkinson’s, researchers were then able to demonstrate the positive effect of UDCA on nerve cells in Parkinson’s Disease.

Testing drugs like UCDA, which are already approved for other uses, can save years and hundreds of millions of pounds. 

From bench to bedside - taking fundamental science into a clinical trial 

The ground-breaking trial, led by Professor Bandmann in partnership with Sheffield Teaching Hospitals NHS Foundation Trust, is now assessing the safety and tolerability of UDCA in Parkinson’s patients. “After nearly a decade of research we are extremely pleased to have launched the first clinical trial of UDCA in Parkinson’s patients to see if the drug is safe and tolerated.

This is a pilot trial, which, if successful, will lead to a bigger study to firmly establish the effectiveness of the treatment to slow down the progression of Parkinson’s. 

A drug which will slow down the progression of the disease – even after the first few years of diagnosis – would help people to have an improved quality of life for longer.”

The study recruited its final patient in September 2019, with a total of 30 participants. To improve the outcomes of clinical trials it is fundamentally important to be able to evaluate them. Researchers utilise advanced technology including wearable sensors to assess patient mobility in everyday life, in-depth gait analysis and the latest in medical imaging. This allows them to take the results from the trial back to the lab to examine whether the drug successfully rescues the mitochondria. 

This trial is the first step in understanding the drug’s potential to slow Parkinson’s progression. 

The future of personalised medicine

Advancing a potential treatment into a clinical trial shows promising progress towards a treatment. But we need to continue to work on disease models to better understand the cells that are driving Parkinson’s. This is the only way we will be effective in stopping progression of the disease. 

Dr Mortiboys is now expanding her work into other mechanisms of Parkinson’s Disease. “Our work on mitochondria is an example of pioneering academic-led drug discovery from bench to bedside. But it's unlikely that there will be one drug that works for every patient. Whilst we have advanced potential treatments for patients where mitochondria are identified as the root cause of the disease - this won’t be the mechanism that is driving everyone’s Parkinson’s so different treatments will be required.”

A recent study has identified two different abnormal mechanisms that underpinned the development of the disease in two different groups of patients with the common sporadic form of Parkinson’s Disease. The study was carried out in collaboration with the University of Oxford and is the largest study to date to use patient tissue from skin biopsy samples from people living with Parkinson’s Disease.

The two groups displayed either mitochondrial or lysosomal dysfunction. The findings of which could be a crucial catalyst to discover new personalised drug treatments.

Professor Bandmann adds: “We also want to study inflammation as a further important mechanism in Parkinson’s. The inflammation in the body of people with Parkinson’s may spread from the gut through the body until it reaches the brain. This should give us new opportunities to stop the illness from getting worse – by stopping the inflammation in the gut, we might also cure the inflammation in the brain!”

Professor Bandmann expects that the evolving concept of personalised medicine will play a big part in the next 10-15 years of research. “At Sheffield we are focusing on understanding why Parkinson’s progresses differently in each patient and using this information to deliver treatments. This is where our fundamental link between clinicians delivering treatments and scientists investigating the disease is vitally important. It is this ability to span research from basic science and in-house drug discovery to clinical trials that makes the University of Sheffield the leading institution to pioneer new treatments for this disease."

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Further information

The National Institute for Health Research (NIHR) Sheffield Biomedical Research Centre (BRC)

The NIHR BRC is a research partnership between the University of Sheffield and Sheffield Teaching Hospitals NHS Foundation Trust, dedicated to improving the treatment and care of people living with chronic neurological disorders.

The National Institute for Health Research (NIHR)

The National Institute for Health Research (NIHR) is the nation’s largest funder of health and care research. The NIHR was established in 2006 to improve the health and wealth of the nation through research, and is funded by the Department of Health and Social Care. In addition to its national role, the NIHR commissions applied health research to benefit the poorest people in low- and middle-income countries, using Official Development Assistance funding.

Funders

• Parkinson’s UK
• Wellcome Trust 
• Norwegian Parkinson Foundation.
• Parkinson’s UK Virtual Biotech
• Rosetree’s Trust
• MRC
• MRC DiMen scheme
• JP Moulton Charitable Foundation
• The Cure Parkinson’s Trust 
• PRO.MED.CS.

Partners

• NZP UK Ltd
• Professor Tom Foltynie at University College London Hospitals
• University of Sheffield’s Institute for Insilico Medicine (Insigneo)
• Dr Chris Elliott, University of York
• Professor Sylvie Urbe, University of Liverpool
• Parkinson's Patient and Public Involvement Groups