Gene therapy - Cystic fibrosis, blindness and more

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.

Have you ever seen a mouse with a mohawk, or mohican, hairstyle? Scientists at New York University's Langone Medical Centre noticed some mice with unusual mohawk-like hairstyles - the result of over-grooming by their fellow animals - and investigated further, as this kind of repetitive behaviour is a hallmark of the human developmental condition autism.

Publishing their results in the journal Nature, the scientists were studying mice that had been genetically engineered to lack a gene encoding a protein called Cntnap4. The protein was previously known to be involved in special brain cells called interneurons, in people with autism. The team discovered that knocking out Cntnap4 affects two special chemical signals in the brain, called GABA and dopamine, which send messages between nerve cells.

They discovered that the mohawk mice had less GABA, which normally damps down signals in the brain, and too much dopamine, which gives pleasurable sensations. The researchers think their findings might shed light on some of the underlying biological processes in the brain that are at work in people with autism, and potentially point to treatments in the future.

And finally, researchers have deciphered the genome sequence of the blind mole rat - an unusual underground creature that lives for more than 20 years and appears to be resistant to cancer. Writing in the journal Nature Communications, the researchers from an international team encompassing the UK, Israel, China, the US and Denmark believe they have found the genetic signatures revealing the secret of their tumour resistance.

Rather than damaged and faulty cells committing suicide through a process called apoptosis, as they do in most mammals, the blind mole rat's immune system directly attacks cancerous cells and destroys them through a process called necrosis. The researchers found that genes involved in this immune defence have been copied and favoured in the mole rat genome over evolutionary time.

It also looks like one of the key players in protecting the body from cancer through apoptosis - a gene called p53, or the so-called "Guardian of the Genome" - is changed in the blind mole rats as part of their adaptation to life in low oxygen. So there seems to be a trade-off between losing the p53 defence, but stepping up an alternative protection mechanism.

The researchers plan to continue probing the blind mole rat's genome to find more secrets that could help shed light on many human diseases, including cancer.

Harriet - Listener Martin Richards asks, "Given that all life on earth is supposed to be descended from a common source, how many genes do I share with a blade of grass? Here's Dr Aylwyn Scally from the Department of Genetics at the University of Cambridge...

Aylwyn - When we ask about shared genetic information between species, in other words, when we compared the DNA sequences or genomes of one species with another, we're really asking about the common ancestry of those species. So for example, with humans and chimpanzees, when we look at the chimpanzee genome, about 99 per cent of it matches up with some place in the human genome. And that's because chimpanzees are very close in evolutionary terms to us.

The common ancestor was about 6 million years ago - a long time for us, but short time for evolution. We go a bit further back to the common ancestor of say, humans and mice, that's about 10 times longer ago. There's been a lot more time for divergence and then we find only about 75 per cent. About 75 per cent of the mouse genome can be matched up almost exactly with some area in human. When it comes to comparing humans or any animal with a plant such as grasses, we're then talking about a much, much greater gulf in time, around about 1.5 billion years.

As you might expect, there's very little that remained unchanged in the genomes of either lineage since that time. Trying to make the same comparison that I just talked about, around about 25 per cent is representative thereabouts of the kind of similarity at that scale. However, we can relax the constraint somewhat. We look for similarity which is not exact, but nevertheless, close enough that there's similarity in function between regions of the genome. Then when we look at plant genes, we can find over half of them have some recognisable counterpart in humans. And that's presumably because those genes had an important role in the common ancestor and continue to do so in their descendants.

Kat - Thanks to listener Martin Richards, Cambridge University's Dr Aylwyn Scally and Harriet Johnson.