Lesley Jones, Cardiff University
Huntington's disease is a rare but devastating genetic illness, affecting up to ten in every hundred thousand people. Sufferers carry a faulty version of a gene containing a region with three letters of DNA repeated over and over again. Fewer than 35 of these repeats and you are probably fine. But 36 or more and you'll develop the disease.
But although researchers know that the number of repeats is broadly linked to how early someone will develop Huntington's - the more you have, the earlier you'll get it - it's still highly variable, so there must be other factors involved. Now, thanks to the largest ever study of the genetics of Huntington's disease, Lesley Jones from Cardiff University and her colleagues have tracked down a number of genetic variations that affect the age at which people develop the condition, opening up exciting new avenues for future therapies. She explains to Kat Arney...
Leslie - So, there’s been a huge amount of work in the biology of huntington’s disease, and essentially, pretty well every biological pathway that you might be interested in appears to be altered in cells that carry the mutation that causes the disease. So, it’s been really hard to pick out which pathways you should address in order to provide a treatment for the disease.
Kat - And what do you find? Who are your prime suspects?
Leslie - So, our prime suspects are a set of proteins that appear to be contributing to things like DNA repair. So they’re proteins that actually operate on the DNA itself.
Kat - What sort of level of change are we talking about? What sort of influence do these variations have on when someone is likely to get the disease?
Leslie - So, we found a particular locus on chromosome 15. And there’s several genes that are very close to this variant and actually, interestingly, there are two variants in this particular part of the genome. One of which, would tend to give people up to six years earlier onset of the disease. This is relatively uncommon, and another variant which is much more common, which appears to give a protection against the onset of the disease of perhaps, between one and one and a half years. But the fact that they occur close together makes us more confident that this is a real effect we’re looking at here and that it’s important in the disease.
Kat - And of course, the big question is, how can we then use this knowledge? The fact that DNA repair kind of molecules are important – how can we use this to find ways to treat the disease?
Leslie - The way that we can use this is to focus our attention on this pathway, rather than many of the other pathways that we’ve been looking at over the years. Because essentially, if you like, nature’s done a natural clinical trial as one of my colleagues always says, for us. It’s lets us know which of the pathways we need to intervene in in order to alter the age of onset of the disease. In other words, this gives us the potential to delay the disease. So, we think that if we try to address DNA repair, we might be able to alter the age at which people get the disease and to push it backwards. Now, altering DNA repair – it’s a pretty fundamental process – and I think it’s going to… it won’t be straight-forward, I don’t think. But people are already looking at these processes because they’re important in cancers. There are one or two drugs potentially that, while they might not work immediately, they would provide a basis for further work to see if we can generate new compounds that might be suitable for manipulating this system in Huntington’s disease. But essentially, we need to understand the biology better and this gives us a chance to investigate that biology in much more detail because we know exactly what we should be looking for, and that always gives you the chance to look at molecules that might alter those particular pathways because you know exactly what you’re looking for.
Kat - Huntington’s disease is caused by these triplets, these three letters of DNA being repeated and repeated. Are there other diseases that are similar that might also be affected in the same way by these same DNA repair processes?
Leslie - There are indeed. So, there’s a series of diseases that are caused by expanded repeats. Most of them are triplets but not all of them. So, there are other diseases that could very well be affected by this same mechanism. Yes. And we’re actually investigating this at the moment.