HL: You're listening to a Medical Research Council podcast with Hazel Lambert. I'm at the MRC Prion Unit with Dr Giovanna Malllucci who's developed a therapy which prolongs life in mice with prion diseases. Can you just explain what a prion disease is?
GM: Prion diseases are fatal neurodegenerative diseases, in other words they kill brain cells and they kill the animal. They exist in all mammals and in humans as Creutzfeldt-jakob disease or CJD or variant CJD which is derived from the BSE epidemic in cows.
At the heart of the disease process is the conversion of the normal protein that is in all brains into abnormally shaped form and that abnormally shaped form is called PrPSc and it accumulates around brain cells and is associated with the loss of brain cell function and brain cell death that then causes the diseases.
HL: Your research focuses on prion proteins that occur naturally in the brain, why study them instead of infectious prions?
GM: You can't get PrPSc unless you've got the normal native protein which is harmless PrPSc. So there's a conversion of a harmless to a harmful or at least disease associated form during the disease process. So in our previous work rather than tackling the abnormal form as has been quite a convention route in these diseases. We genetically engineered animals to lose the native form, the normal form, working on the assumption that if you haven't got the building blocks for the disease you can't get it. So it really underpinned a strategy that's been used in the unit which is to target PrPc to find molecules that stop PrP being involved in the disease process. HL: How have you targeted the normal native prion protein, the PrP in this research?
GM: What we did was we took advantage of developments in gene therapy using a system called RNAI or RNA inhibition. This is a way of knocking down gene expression.
HL: What does that mean?
GM: For a protein to be made a gene needs to be expressed and a gene is essentially a sequence of DNA that is transcribed into RNA and the RNA is then translated into protein. But what it exploits is the fact that small sequences of RNA that are complimentary to the special message for the protein can degrade that message so the gene is expressed at an RNA level but it's never translated into protein, so you eliminate the messenger basically. HL: How do you get these RNA strands into the brain?
GM: You can put them into a carrient structure and we use modified viruses for this. They've been modified so that they're not infectious or pathogenic, they're just carriers and these viruses integrate into the brain cell's DNA and stay there and they continuously express the short sequences of RNA that are going to do the job. So this means that you only have to do it to them once. So what we did was we made viruses expressing short, they're called hairpin RNAs that targeted PRP, the native protein, we injected these into prion infected mice, only one injection on each side of the brain into a very small region called the hippocampus. And we chose that region because it's the region that we've previously seen recovery and it's a region that you can test for memory and behavioural changes. HL: What effect did introducing the RNA have on the mice?
GM: What we found was that by injecting these viruses at a relatively early stage of the disease, we were able to protect those neurones, brain cells, that were targeted from the disease process. So they were protected from the spongiform or holy change that happens in prion disease. Neurons weren't lost, there was no brain cell death in that region and it protected them against developing the memory and behavioural problems that happens at that stage in prion disease. And also the mice survived up to an average of 25% longer; now some of those mice survived nearly 50% longer with a single targeted area. It's exciting because even this very focal delivery has beneficial effects both on survival of neurones, function of neurones and also potential on longer term survival. HL: Does this mean that viruses could be used to deliver RNA as a form of therapy for people who have prion diseases like variant CJD?
GM: It's a very, very long way off for a sort of human brain targeting but I think really what it's given us is a tool to ask them different questions about the evolution of prion disease; it's almost a tool to ask more questions rather than an early form of a deliverable treatment. HL: Dr Molucci, thank you.
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HL: Hazel Lambert GM: Dr Giovanna Mallucci
