Case study: Professor Frances Platt

Research: Searching for new treatments for a set of inherited diseases that result in neurodegeneration and early death.

Animals used: mice

Professor Frances Platt: ‘Lysosomal storage diseases are a set of 50 different disorders, the vast majority of which affect the brain. They most often result in a relentless and devastating decline in neurological function and early death, often in infancy and childhood.

‘While individually rare, together they affect as many as one in 5000 live births.

‘They are genetic diseases that occur when a child inherits a mutant gene from both parents. The child will have a deficiency in an enzyme that causes a particular type of molecule to build up in the cells of the body. The molecules are stored in parts of the cell called the lysosome, which gives the diseases their descriptive name: lysosomal storage diseases. I study a sub-group of these diseases in which fatty lipids that have sugars attached to them are stored.

‘Those with the disease tend to be born completely normal, but children may then begin to fail to meet certain developmental milestones as they get older. There can be a very rapid build-up of the molecules in some people leading to disease in early childhood, and there are also milder forms of the disease that don’t develop until adulthood. These adult-onset patients develop symptoms in their 20s, 30s, 40s, or 50s.

‘The diseases are hard to diagnose and being referred to the right person, often a paediatric neurologist, is key. Unfortunately, because of the range of possible symptoms and the variation in severity of the disease, it can take several years for a correct diagnosis.

‘We don’t understand all the factors that cause the differences in the age of onset of the disease, but progression of the disease is relentless once it begins. We don’t even understand what the molecules normally do in cells (what their function is), or why the build-up leads to such devastating effects in the brain of people with these disorders.

‘My research group is interested in how the accumulation of these sugar-lipid molecules triggers the cascade of events that leads to the disease, and how we can devise new therapies to combat this.

‘We found that a drug called miglustat stops cells from making the problematic molecules in the first place. If the cell cannot make as many of these molecules, then the build-up stops or at least takes longer to occur. The hope is that the disease will be stopped or slowed in its progression.

‘We started our experiments in tissue cultures in the lab, before moving on to mouse models of lysosomal storage diseases, and showed that the lifespan of the mice was extended by 40 per cent. Full-scale clinical trials with the backing of clinicians and pharma companies then demonstrated clear-cut results. We are certainly impacting the disease with this drug, and it is now approved in the EU and US for treatment of Gaucher disease. A clinical trial of the same drug in Niemann-Pick type C disease patients has recently shown that this drug is disease modifying in this severe neurodegenerative disorder.

‘Having this drug also allows us to go back and dissect some of the cellular changes that go on in these diseases. In Niemann-Pick disease type C, we have been able to show that the disease affects how the cell uses calcium.

‘This gave us a new therapeutic approach to try. We are now looking at curcumin, a natural product from turmeric that is used in curries, which elevates the level of calcium in the cell. Niemann-Pick type C mice given curcumin do better than they would otherwise. We are now moving towards working with clinicians to show whether curcumin has a benefit in the human disease.

‘It may be that combination approaches are the best way to help patients with these diseases. It may be possible to combine drugs like miglustat with anti-inflammatory drugs that mitigate symptoms, and natural products like curcumin that target a different aspect of the disease.

‘The mouse models of these diseases have either spontaneously occurred due to mutations in healthy mice or have been modified to have the same genetic mutations as in the human disease. In this group of neurodegenerative diseases, the mouse models provide very good mimics of the human conditions and have similar clinical features.

‘In the trials of new therapies in the mouse models, one group of mice will receive no treatment and another will receive a drug orally (there are no invasive procedures). We have developed a set of behavioural tests – for example that look for the mouse’s ability to do tasks, their coordination and exploration – that are a sensitive measure of the stage of disease. This means we don’t have to kill mice to follow disease progression, and groups of five mice can give an answer rather than much larger groups. When the mice get close to dying, we humanely put the mouse to sleep then take tissues for biochemical analysis.

‘If there was an alternative to using mice, we would use it. A lot of work is done in tissue cultures for example. But we could not show a therapy worked without mice. In a typical paper from our group, only one figure will show the result of work with mice while nine out of ten will involve cultured cells.

‘There are lysosomal storage diseases that affect animals too – sheep, cows, dogs, cats, deer, even emus – so there is veterinary interest in these results. There are now five or six companies looking at developing therapies in this area.

‘The new Biomedical Sciences Building has made an enormous difference to our work. It is better for the animals’ welfare and care, and better for the science.

‘With the new building, animals are housed in state-of-the-art facilities. Vet care and supervision is now all in the same place, so that all the people with animal care, welfare and procedures knowledge are right there with you to offer advice on best practice.

‘While our previous building was fit-for-purpose, it wasn't ideal. Things are much better now since the move to the new facility.'