Prof Jane Davies - CF gene therapy

Kat:: Another area where gene therapy could potentially bring big benefits is cystic fibrosis, or CF - a disease caused by a faulty gene called CFTR, which affects around one in every 2,500 babies born in the UK.

Professor Jane Davies, at Imperial College London, is involved in a major UK trial of gene therapy for cystic fibrosis. She explained how the disease is caused, and how gene therapy might be able to help.

Jane:: Cystic fibrosis is what we call recessive condition which means that if patients have just one copy of an abnormal gene, they can be completely healthy and are carriers.  But if they inherit two copies, i.e. one copy from each parent of the faulty gene, then they have cystic fibrosis.  In normal health, what the cystic fibrosis gene does is it generates a protein which is very important in lots of cells in the body for shuttling salts in and out of cells.  The reason that that's important is because water tends to follow salt wherever it goes.  And so, particularly in organs such as the lungs and the digestive system, the surfaces of those organs are dehydrated and extra sticky and dry.  With regard to the lungs, bacteria can get in there, set up infection, and inflammation follows infection and then we get lung damage which ultimately leads to respiratory failure.

Kat:: In terms of gene therapy, you think, "Well, that's great!  We should just be able to fix that faulty gene."  I guess that's the idea.  How do you approach doing that in practice?

Jane::  So actually, fixing the faulty gene is extremely difficult and what most people with gene therapy are trying to do for cystic fibrosis is ignore the faulty gene but put a copy of the healthy gene into the cells next to it.  The faulty gene itself doesn't matter.  So, we're sort of taking over the work that the faulty gene should be doing by putting a copy of the healthy gene into the cells.  The way in which we try and do that is directly into the airway by breathing in, usually a mist solution - some people have tried to do it with other liquids down bronchoscopes and that sort of thing.  We're trying to get normal copies of the gene into the cells by coupling them up with things that we call vectors.  The vectors are just little transport systems that carry the gene across the cell surface into the cell and then into the nucleus where it needs to do its work.

Kat:: Like little postman really, just delivering the healthy gene into the cells where they need it.

Jane:: Exactly like little postman.  The two types of postman that people have used are viruses that have been specially modified to not infect the body, but to carry the healthy gene along with their own genes into cells and then synthetic methods such as liposomes which is the route that we are going down.  The benefit of the latter is that the body doesn't respond to the liposome in the same way that it responds to a virus.  Viruses can be very good the first time you use them, but if you try and use them repeatedly, there's a bit like an immunisation response.  So, the body gets used to it and chucks it out before it has time to do its work.  So viruses are really good for certain diseases where you just need to do a one-off hit, like certain cancers.  But for cystic fibrosis, because it's a lifelong disease, we believe at the moment that the best approach is to use liposomes.  We're looking at ways to try and use either longer lasting viruses or viruses that manage to get under the radar of the immune system so that you could give them repeatedly.

Kat:: In terms of where you are currently with trying to get these treatments to work, what's the current state of research?

Jane:: The current state is that overall globally, there have been well over 20 trials of gene therapy for CF but the vast majority of them have been a single dose often into the nose, sometimes into the lung.  But looking for proof of principle: can this little postman get this gene into the cell and make the cell's behaviour a bit more like a healthy one rather than a CF one.  The measurements for those sort of behaviours are not clinically relevant.  So very, very few trials have actually addressed the clinical relevance of gene therapy.  We've just finished that first one that we think has been properly designed to do that where we've taken a large number of patients through repeated dosing over a period of a year.  The outcomes that we're looking for are, do these patients get better in a number of ways that we're looking at it.  We've finished the trial last week.  The data are just being analysed and put onto the database and we'll see whether it's worked which we don't yet know.

Kat:: Obviously, for this kind of gene therapies, if you're just delivering things into the lungs, it's only addressing the problems in the lungs.  Are there approaches that could maybe address some of the problems elsewhere in the body?

Jane:: That's a really good point because it is a multi-system disease.  The pancreas doesn't work properly, the gut doesn't work completely normally.  Some people have liver disease.  So, I think at the moment, because it's lung disease that kills people by and large, most of the gene therapy approach have focused on the lungs.  There are some approaches to trying to make the protein itself work better, forgetting about the gene level, coming down to the protein which can be tackled perhaps by an oral drug.  That's one of those that's been successful and is on the market now, just for a tiny proportion of patients with CF.  That type of approach would have the potential to affect other organs as well.  There is at least some suggestion that the gut might be helped by those sorts of oral drugs.

Kat::  Obviously, for families with children with cystic fibrosis who are really desperate for something that's going to make a difference, are you positive that this kind of approach is going to payoff in the end?  If so, when would you really like to see it making a difference to patients' lives?

Jane::  I'm very, very hopeful.  We wouldn't be doing it if we weren't hopeful.  But I think it would be absolutely misleading to say that I'm positive it's going to pay off.  We're going to know the results of this trial in September.  We could find out that it hasn't worked at all and then we're back to the drawing board in terms of our next wave of trying to get things to work or we could find out if it's worked marvellously well.  If it has then that could potentially be quite a small leap from the end of that trial through phase 3, into clinical benefits.  But there's such a big gulf between those two scenarios that I think it would be really foolish of me to say I'm certain or I know when it's going to work.  I think that what's very, very encouraging within the last two years, we've had the first proof that you can actually make the protein work and if you can do that, you can make patients substantially better.  And that's come from some of these small molecule drugs.  So, if we can get enough of the gene therapy into the cells to produce the protein then we know that that should work.  But there's quite a lot of ifs along the way there.

Kat::  Obviously, with something like gene therapy, there's a lot of science behind it.  There's also a lot of clinical time, doctor's time, and patients and their families.  How great has the input been here in the UK from the research community and the patient community?

Jane::  So it's been absolutely fantastic.  I work at Imperial College and we're part of the UK's CF gene therapy consortium, working with colleagues at Oxford University and Edinburgh University and hospitals.  The trial that we've just completed has been an enormous effort for ourselves, fantastically supported by our funders, but also the amount of time and help that the patients and their families have put in.  Many of them travelling from lots of different cities to our study sites to actually help us with the trial has been absolutely fantastic.  We couldn't have achieved this without them.  So, we're incredibly grateful.  Of course, they and we are very, very hopeful that the outcomes are going to be positive. Kat:: That was Professor Jane Davies from Imperial College.