You need the latest Flash installed and Javascript enabled to view media on this page. Please ensure Javascript has been enabled in your browser settings. You can download Flash with the link below.
Get Flash Player now
Dr Liv Hibbitt: 'Familial hypercholesterolaemia (FH) is an inherited condition caused by a genetic mutation in a protein that takes “bad” cholesterol out of the blood. Those with the condition tend to have high levels of cholesterol, develop artherosclerotic plaques (hardened arteries), and die from a heart attack or heart disease.
‘FH, although often thought of as a rare disease, actually affects around 1 in 500 people. It typically occurs when one normal copy of the gene is inherited from one parent and a defective copy is inherited from the other. It tends to be first diagnosed when someone goes to their doctor after a heart attack in their late 30s or 40s and a genetic test is done. Patients normally die in their 50s.
‘Treatment normally involves statins, drugs that turn up the working copy of the protein to remove more cholesterol. It is also possible to change diet to lower cholesterol, but only around 15 per cent of circulating cholesterol in the body is due to diet.
‘Gene therapy involves using a gene like you would use a drug. We’re not trying to replace the defective gene, but give the body an extra working copy of the gene. The aim is to deliver the gene to the cells in the liver where it is needed.
‘Gene therapy would be particularly appropriate for FH because there are not many existing treatments and they’re not very effective. It’s also a “loss-of-function” disease like cystic fibrosis or haemophilia, where we can hope to introduce a gene that will restore that function. If we introduce a gene to produce more copies of this specific protein, it should start taking bad cholesterol out of the blood again.
‘People have been working on this area for years and years, and two Nobel prizes have been awarded, but no one has got anywhere with gene therapy for FH. ‘The problem is that the amount of the FH protein is carefully regulated according to how much cholesterol there is around in the body. Previous attempts at gene therapy have used gene regulation elements from viruses which result in lots of protein being made. Unfortunately, too much protein triggers the cells to die and levels of cholesterol quickly rise again.
‘We are using the DNA regions from humans to regulate the FH protein in the physiologically appropriate way. These are longer sections of DNA and means a lot more DNA has to be delivered to the cells in the gene therapy. But we are finding ways of doing this.
‘In working towards a gene therapy treatment, we are at the stage where we’re writing a grant to do an animal study. We have got a delivery system that works in cells, ie we’ve done tissue work in the lab. If we give the cells statins, we see more protein produced after we’ve delivered the gene. And if we give sterols, we see less protein produced, as we would expect.
‘We’ve also developed a way of delivering genes to the livers of mice in such a way that we can see them using a special camera. We use a gene from a firefly that glows and the camera is able to pick up the light that emerges from the mouse’s liver. This drastically reduces the number of animals we would need to use otherwise. Previously, we would have had to kill mice at different time points to determine the gene expression. Here we can put the gene in and monitor on a weekly basis without having to kill any animals. It’s really non-invasive – we give an injection into their tummies under anaesthetic, and they’re running around again five minutes later. Rather than use 200 animals, we have used 20 mice to optimise the experiment and find the best possible way of getting the gene in.
‘Now that we have a method that works, we can hopefully move on to a mouse model for FH.
‘We breed and maintain a colony of “knockout” mice (mice with one gene removed) that are defective in the same gene that removes cholesterol from the blood. Although the mice don’t develop artherosclerosis, we are able to tell if the gene has been delivered and is being expressed as desired.
‘Breeding is as much as we do for most of the mice, but a small number do receive an injection under anaesthetic as part of a trial. Some mice are then imaged with a special camera, again under anaesthetic, and others have blood samples taken from their tail at different times.
‘The Biomedical Sciences Building is fantastic for welfare purposes. Any problems, such as animals not getting on or animals being born with cataracts, and I need to be there immediately to sort it out. If there are any animals in distress at all, I want to be there immediately. Previously, my work was divided between three different centres. With one building I am able to visit it daily and look after the animals. Also it is great that the vets are now in the same building offering their support.
‘I am using mice because I have exhausted all other techniques. I have done everything I can in cells and on computers.
‘Once treatments in development move into animals, it is a whole different story and it can’t be predicted how well they will do. For example, we initially started with large vectors (a vehicle used to deliver genes in molecular biology) that worked fine in cells. It turned out it was no good in mice – it didn’t hit enough cells and so not enough protein was produced. Efficient delivery is necessary to see an effect. We didn’t know this until we did the first experiment in animals.’
