- Lead researcher: Dr Heather Mortiboys
- Location: University of Sheffield
- Cost: £419,312 over 5 years and 9 months
- Start date: September 2013
- Type of project: Career Development Award
- Project code: F-1301
People with Parkinson’s don’t have enough of a chemical called dopamine because some cells in their brain have died. Almost all current treatments for Parkinson’s focus on replacing dopamine. These treatments help to manage the symptoms but become less effective over time, cause troublesome side effects, and cannot slow or stop the condition.
- Finding new uses for drugs that are already used for other conditions has great promise for quickly bringing new treatments to people with Parkinson’s. These drugs are already widely used so can enter clinical trials quickly. And this approach has already successfully identified diabetes drugs with potential for Parkinson’s.
- Heather Mortiboys is looking for drugs that can improve the function of two key players inside cells that are known to stop working properly in Parkinson’s. Previous research has shown that the mitochondria, the energy-producing power stations inside cells, do not function properly. Normally, when mitochondria stop working properly they are removed by the waste disposal system of the cell which is called the lysosome. But blockages in this system also seem to occur in Parkinson’s.
Progress so far
Heather’s project is focused on identifying drugs that are already used in other conditions with untapped potential for Parkinson’s by looking to see if they can improve the function of mitochondria and lysosomes, and therefore slow or stop the loss of brain cells. As a first step, Heather made a list of 4000 drugs which are already used to treat other. She then took the top 224 ranked drugs and tested them on skin cells from people with an early onset form of inherited Parkinson’s, people with late onset inherited form of Parkinson’s, and people with the condition who do not carry any genes known to increase risk.
On analysing the vast amount of data produced Heather found 23 different drugs which had potentially beneficial effects on mitochondria and/or lysosomes in the skin cells. Heather tested these drugs further using other methods and different doses to be sure the drugs really did have a beneficial effect.
Heather has found three groups of drugs which have beneficial effects on both the mitochondria and lysosomes in patient skin cells. Importantly two out of the three seem to work in all the different types of skin cells which means they may be beneficial for most people with the condition. The third group of drugs works in the group of patients who carry a mutation in a gene called LRRK2 which is linked to an increased risk of Parkinson’s.
Heather next wanted to investigate how these groups of drugs were protecting the mitochondria and lysosomes and find out whether they have real promise as treatments for people with the condition. To do this she and her team have made brain cells by reprogramming the patient skin cells. This means they can test the three groups of drugs in brain cells that are very like those that are lost in Parkinson’s.
They have found that the drugs can increase a process where damaged mitochondria are broken down (known as mitophagy), back to normal levels in the brain cells they made. They have also investigated which mitophagy pathway the drugs could be activating.
What are the next steps?
Heather Mortiboys will be continuing her work to find out exactly how the drugs are having beneficial effects on the mitochondria and lysosomes. Once they know how the drug is working, they can then find a way of to measure the effects of the drug in people, which would be important before the drug could be tested in clinical trials.
How the research will help people with Parkinson’s
If Heather is successful and finds strong evidence that any of these drugs have real promise, she plans to take them forward as rapidly as possible to be tested in a clinical trial. Ultimately Heather hopes her work will lead to better treatments that can slow or stop the development of Parkinson’s, and because she is studying drugs that are already widely used for other conditions this could be a reality in years rather than decades.