Creating drugs to restore mitochondria and stop Parkinson’s

Parkinson’s UK is investing up to £1.2 million into a pioneering 1-year project in partnership with the University of Sheffield. The project aims to take important steps towards creating a drug that can protect dopamine-producing brain cells and slow down the progression of Parkinson’s.

This important project is funded through our Parkinson’s Virtual Biotech initiative, which exists to fast-track the development of new treatments for people with Parkinson’s.

We’re delighted to be joined on the Parkinson’s UK Research Blog by lead scientist Dr Heather Mortiboys to tell us more about this exciting research.

What are mitochondria and why could drugs that restore them be the key to slowing or stopping Parkinson’s?

Mitochondria are like tiny batteries that are present in almost every cell in our bodies. They are responsible for producing the essential energy that our cells need to function properly and survive.

Brain cells need lots of energy. And the dopamine-producing brain cells that become damaged and lost in Parkinson’s are among the most energy hungry because they are so large and complex with lots of connections to other brain cells.

It has been known for some time that mitochondria seem to stop working properly in these dopamine-producing cells in Parkinson’s and that mitochondrial problems seem to happen in almost all forms of the condition.

When mitochondria stop working properly the cells don’t have enough energy to do their jobs properly which causes lots of problems. To make matters worse, faulty mitochondria seem to build up inside these brain cells, releasing toxic chemicals that poison the cells causing even more damage.

For these reasons, I and many other scientists believe that if we can develop drugs that can get mitochondria back to being healthy and working well we could slow or even stop the progressive damage to brain cells in Parkinson’s.

How are you trying to develop these drugs?

I received a Senior Research Fellowship from Parkinson’s UK in 2013 and that enabled me to set up my own research group here at the University of Sheffield’s Institute of Translational Neuroscience (SITraN) and really focus my research on mitochondria in Parkinson’s.

I became a scientist because I wanted to develop treatments that could really make a difference to peoples’ lives. And as well as receiving funding from the charity, I’ve also been hugely inspired by getting to know and work with the Parkinson’s community. Not only is their passion for research and their interest in our work incredibly motivating, but discussing my work with them has actually helped shape the experiments that I do to make my research more relevant to people with Parkinson’s.

I’ve now been studying mitochondria in Parkinson’s for almost 20 years. In that time we’ve made some really important steps towards finding drug-like molecules that can fix the problems that we see with mitochondria in Parkinson’s.

Crucially we use skin cells taken from people with Parkinson’s that we can grow into brain cells in the lab. Importantly, when we study these cells from people with Parkinson’s we can see that they have problems with their mitochondria. Just like those that happen in the cells in the brain in the condition.

We use these precious cells to test drugs already in clinical use that might have a beneficial effect on the mitochondria. This is a new way of working in drug discovery, most drug discovery work does not include testing in cells from people with Parkinson’s so early in the pipeline. We tested thousands of these molecules and found a handful that seemed to have really exciting positive effects.

So what’s happening with this new Virtual Biotech project?

Repurposing existing drugs is hugely important because we know these drugs are safe for people to take and therefore they can be more rapidly taken forward into clinical trials in people with Parkinson’s. Ultimately, if they are proven to be effective, they could be made available quickly.

However, while repurposing drugs holds great promise, because these drugs haven’t been purposely designed for Parkinson’s there is likely to be room for improvement. By that I mean, can we take a drug that shows promise and then use it as the inspiration for an entirely new drug molecule that could be even more effective?

That’s what we are attempting to do with this new Virtual Biotech project: take some of the drugs we identified in my research and improve on them to hopefully produce a drug that is the best that it can be. We found that these drugs are boosting mitochondrial function by working in a new way, but they also could cause some side effects that we wouldn’t want when given to someone with Parkinson’s.

We started working with Richard Morphy who is a Drug Discovery Manager at Parkinson’s UK and an expert in medicinal chemistry in 2018 to see whether it would be possible to create new molecules from the drugs we originally identified.

Over the past year, we’ve successfully created new molecules that seem to be very effective at addressing mitochondrial problems in Parkinson’s and they do not have the activity which would cause the unwanted side effects of the original drugs.

This initial success has now led Parkinson’s UK to invest a further £1.2m to take these molecules forward and try to develop them into drugs that could be tested in people with Parkinson’s in future.

Over the next year, we plan to develop our molecules further to produce a molecule that can restore mitochondrial function in our cells from Parkinson’s patients as well as having the ability to get from the bloodstream into the brain. This is a crucial factor in creating a drug that can be given in a pill.

If we’re successful, we’ll then be ready to start testing in animals to understand safety and effectiveness which would be an important step towards taking it forward into clinical trials in people with Parkinson’s.

It’s a painstaking process and there is a lot of work and rigorous testing to be done but I’m incredibly excited about what the future holds.