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The Gene Race
was broadcast on 5 February 1996.
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Programme Notes At 21, Sean Conroy is nearing the end of his short life. He says he feels fine. He never talks of dying, but his life is a daily battle against the inherited, incurable lung disease, CF - cystic fibrosis. But there is one last hope for sufferers like Sean. The race is on to find a cure.Instead of working against the symptoms of CF, a few scientists are now trying to correct its fundamental cause. They want to introduce new genetic material into the lungs of their slowly dying patients so that it can take over the biological job which their own genes do so badly. This is gene therapy, the great hope of the genetic revolution. Successful gene therapy for cystic fibrosis will bring longer lives to thousands of sufferers, academic acclaim to the successful scientists, and about $1 billion to the company that gets it first to market. However, while the promise of gene therapy has been touted for many years, it doesn't yet work for any disease, no one has yet managed to put new genes into a person and make them work as they should. The race is still on.
Judith Bunting's moving and intimate film, The Gene Race, tracks the vital progress of two research teams as they begin human trials of their radically different genetic techniques for treating cystic fibrosis.
In America, Ron Crystal is using a genetically modified common cold virus to carry the new gene into his patients. This approach exploits the fact that the cold virus has spent thousands of years invading human lung cells. But there are significant risks attached. With their lungs weakened by years of disease, someone with cystic fibrosis can be killed by a cold.
In London, Bob Williamson and Duncan Geddes and their team have chosen to deliver the gene to their patients' lungs in droplets of fat called liposomes. These should be less risky than a virus; they are widely used in cosmetic moisturising creams. But before the team are allowed to use their mild liposome/DNA package in the lung, the British authorities insist that they conduct safety tests in the nose.
With unprecedented access behind the scenes, The Gene Race chronicles the ups and downs at the cutting edge of medical research. As the race to implant a functioning gene in the vulnerable CF lung accelerates, the programme gives an insight into why gene therapy is taking such a long while to arrive. It reveals the frustration of waiting for official approval, what happens when a patient falls ill and one of the trials has to be stopped, and the reason why the man who kick started gene therapy in Britain quits the country and the NHS just when things are looking good.
And alongside everything runs the tragic story of Sean, a guinea pig in the British trial, for whom this cutting edge treatment has come too late.
Programme Transcript DUNCAN GEDDES:
Everybody who's working on this would like to be the team who comes up with the best treatment quickest.DR. ALAN SMITH:
A successful gene therapy would represent a market of some-where between ½ and one billion dollars so a successful drug here is a big successful drug.RON CRYSTAL:
Let's keep in mind that this is a lethal disease. Everyone, everyone who develops cystic fibrosis dies.SEAN CONROY:
Now the gene therapy's coming along it's almost as though it's like a holiday. You know it's coming and once it's here the sort of medicine would take over the part and fighting it for you.NARRATOR (JACK FORTUNE):
For Sean Conroy it's not about money or being first with a scientific discovery. His whole life is a race to survive.DONNA PEARCE:
I was at a disco. My friend already knew of Sean and she said to me: oh that boy over there he's dying and I was trying to figure out what was the matter with him and after a couple of months he told me he had asthma and I thought oh it's a bit bad for asthma and then eventually went on to tell me and explain to me about cystic fibrosis.SEAN CONROY:
I take every day as it comes. So far I've done 21 years without a scratch and I'm sure I'll be able to double it easy.NARRATOR:
Sean was born with the genetic disease, cystic fibrosis. On average, people with CF survive only until their late 20s, usually dying from lung disease. A single faulty gene upsets the workings of the cells that line their lungs and leaves them highly vulnerable to infections.DUNCAN GEDDES:
The gene in the normal situation it regulates the amount of salt and water that goes across the lining of the lung and that regulates how wet the mucus is and so presumably that allows the mucus to keep the bacteria out. In cystic fibrosis it doesn't work and so the salt and water movement across the lung is abnormal and the easiest way to think of it is the lungs just get dried out.NARRATOR:
Relentless bouts of inflammation and infection, caused by the bacteria trapped in the dry, sticky mucus, progressively destroy the lungs of people like Sean. They can also destroy the spirit.SEAN CONROY:
I had a friend a couple of years ago. He was about 2 years older than me. He had CF. He was quite healthy. He had just as much going for him as me, but one day he sort of just turned round and gave up. He said to his Mum he's had enough and that he's just fed up with fighting the thing. Inside, personally I would have liked to have gone down and physically hit him I suppose 'cos it's stupid, there's no point giving up. Just for the fact that we should see it through and beat it, not let it beat us.NARRATOR:
With less than half his lungs in working order, Sean volunteered to be a guinea-pig in a trial of gene therapy for cystic fibrosis. Gene therapy: an idea that only recently moved out of the realm of fantasy.In a haze of publicity in 1989, the gene that causes cystic fibrosis was identified and with it came a new possibility. If the normal gene could somehow be put into the lungs of young people like Sean, while it wouldn't cure them completely, it could stop them dying so young.
By 1993, several research groups world-wide had embarked on a race to put the gene to use in an effective therapy. The first to start work on human trials was an American team led by Dr. Ron Crystal. They planned to test the good gene on site in their patients' lungs.
RON CRYSTAL:
We went directly to the lung because that's where the lethal manifestations of the disease are. There's a famous phrase in the United States based on a famous bank robber in the 1930s/40s I think in the United States named Willie Sutton who robbed many banks and when he was captured he was asked in an interview: why do you do this, why do you rob banks? And he said: that's where the money is. The reason we went directly to the lung to try to treat the disease with gene therapy is that's where the money is, that's what kills the patients.NARRATOR:
In the heart of London the first team to plan a full-scale trial of any gene therapy in Britain was led by Bob Williamson from St. Mary's Hospital, and Duncan Geddes, from the Royal Brompton.DUNCAN GEDDES:
The key moment was when Bob Williamson and I sat down and decided that the moment had come to actually go forward into designing human trials. Now Bob Williamson had been working on the ideas of gene therapy for a long time before. I'd been working on cystic fibrosis for a long time before.NARRATOR:
While the ultimate target of their work was to be the lung, they decided to test their ideas in the nose first, to make sure they were safe.BOB WILLIAMSON:
If you go right down into the lungs at the beginning in the first place it's a much more traumatic experience for the patients. It involves a bit of anaesthetic, it involves passing a tube into the lung, and obviously it's much less pleasant, but the other thing is: it's much harder to evaluate. In the nose we can go in every few hours, every day, every 2 days, and we can see what's really happening. If there is any inflammation we'll know, this we'll shine a torch and we'll see it, and we'll be able to stop the trial straightaway.NARRATOR:
Another big difference in approach concerned what would actually carry the gene into the patient's cells. The Americans plan to use the Adenovirus, the virus that causes the common cold.RON CRYSTAL:
I'm a clinician as well as a basic scientist and so I'm aware that as a lung doctor that adenoviruses are one of the causes of the common cold and also cause bronchitis and pneumonias, and so the adenovirus clearly knows how to get into the airway lining cells and so the adenovirus as a cargo ship already knows how to do the job.To make sure that it does not do any harm it's simply in molecular terms just some cutting and pasting. What you do is you take out the bad parts of the virus and you put in the normal gene with appropriate controlling elements, and so essentially what you're doing is taking a bad virus and turning it into a good virus. Working on the cutting edge of any kind of technology you have to think about what's the worst possibilities because it's your responsibility is to the patient and probably the worst scenario that we could think of is that somehow the virus we were using would turn into a worse virus, you know sort of like the Andromeda strain in the Michael Crichton novel. We knew theoretically that it was possible that the virus that we had made could somehow recombine with other genetic information and cause perhaps a virus so that we couldn't let the patient leave the hospital. If the individual is a risk to society we would have the obligation to go to a court for example and say we may have to keep this individual in the hospital.
NARRATOR:
A more likely risk was that the patient's immune system would recognise the virus and try to fight it off. If that happened, their lungs could become dangerously inflamed and the patient might die. Thoughts like this guided the approach of the London team.BOB WILLIAMSON:
We were a little worried about using viruses because viruses do cause problems I mean they do cause colds, they do cause flu, they can even cause cancer in some cases, so we were rather keen to get away from giving patients something which we knew if things went wrong could actually create difficulties so we've had to spend a bit of time trying to make sure that we can get the lipid approach to be as efficient as the virus.NARRATOR:
The lipid approach depends on tiny drops of fat called liposomes.COMMERCIAL VOICE-OVER:
We could tell you all about liposomes and their ingredients, but would you be interested? We could even show you what they look like, but would you really care?DR NATASHA CAPLEN:
Well the place where most people have heard of liposomes now is in the beauty industry and we see lots of adverts where they're going to be the latest elixir of life, where what they're trying to do there is incorporate into the middle of a fatty droplet, which is what the liposome is, some latest wonder substance. Why they're using it is that liposomes are, consist of basically the same molecules that are also in the surface of your skin and so in the case of the beauty industry the liposome will help to put this great wonder element into your skin and make everyone look very beautiful. What we've been able to do though is try and use the similar sort of technology, but use it by putting DNA in context with the liposome.COMMERCIAL VOICE-OVER:
Its active natural ingredients are carried by natural liposomes and absorbed into the epidermis.COMMERCIAL VOICE-OVER:
My skin is moisturised, protected and looks younger.NARRATOR:
But using these microscopic drops of fat for gene therapy was a longshot. Not many people in the field took them seriously. They were reckoned to be too inefficient for the job.
RON CRYSTAL:
For every 1,000 genes that you get into a cell, with a liposome only one's going to make it. That doesn't mean that the strategy will not work. It could possibly work eventually and therefore I would encourage these kind of studies to go on that are going on in Britain. I think they're very important. But in its current form, the liposomes are too inefficient to work.DUNCAN GEDDES:
A virus is a very efficient way of getting a gene into a cell, but viruses, as everybody knows, do cause disease.RON CRYSTAL:
Think of the virus as sort of like a laser directly to the nucleus it's going to work, whereas the liposome is sort of a blunt instrument that's not going to work very well.NARRATOR:
Genetic medicine is fundamentally different from any other treatment ever used in the history of medical science, so in both countries gene therapy projects have to be vetted by government-appointed medical and ethical committees to make sure the plans are safe. Getting approval can be a long and frustrating process.DUNCAN GEDDES:
They took a long time because we were the first, or that almost the first, and therefore the mechanisms weren't there and books of rules had not yet been written and that means that any committee who has to make a decision without a book of rules clearly needs to deliberate more.WOMAN:
We are a couple of minutes early, but I think we'll make a start. So welcome to our seventh meeting. Since the last meeting you will know that...DR. PETER MIDDLETON:
Right, OK, now the legal part about all of this...NARRATOR:
Behind the scenes, they also had to get the informed consent of everyone who had volunteered to take part in the trial.PETER MIDDLETON:
...by gene therapy what we mean is taking an engineered gene and putting it into your nose and seeing whether the gene can get into the cells of your nose, and if it does get in, whether it can correct those cells from being CF cells to being normal cells.SEAN CONROY:
If I was to sneeze on Joe Public would it affect them at all, or is it just only to do with our bodies?PETER MIDDLETON:
It's really only to do with your bodies because Joe Public if he doesn't have CF has already got the gene that you've got. Having said that, genes are incredibly unstable and the chances of you actually being able to sneeze and to get it through the air and into him without it falling apart in the meantime is very unlikely. We have to work very hard to actually keep these genes together, to actually get them to you in the first place, so the chances of that happening are very, very slight.NARRATOR:
Ron Crystal had submitted his gene therapy proposal at about the same time as the British. But while they were still waiting for final approval, the American authorities gave Crystal's more aggressive proposals the go-ahead, and the very next day his team became the first to test gene therapy for cystic fibrosis anywhere in the world. The first patient to receive the Adenovirus into his lungs was a 23-year-old young man.RON CRYSTAL:
We were all excited in the sense of like before a big football match. Everybody's a bit tense, a little, excited. I think afterwards and particularly, I don't know whether it's on this tape, we were in a room that was in negative pressure, to the outside atmosphere because we wanted to ensure that if there was any spread the vector would remain within that room. When we came out of the room many of our colleagues were outside and we actually had a TV monitor outside, they were watching it, and actually to my surprise, everybody started applauding and it was I think probably at that time that each of us who were involved with it directly realised that, you know, to everybody that it had some historic importance and in fact you know everybody was pretty excited about it.NARRATOR:
While Ron Crystal's team had started work in humans, other groups in the US were still testing the adenovirus on animals, in particular on baboons. Barely a month after the Crystal trial began, this group released results that raised a few eyebrows about the safety of what Ron Crystal was doing.JIM WILSON:
We have an example here of a chest X-ray of a baboon that received the highest dose of the virus. This represents the rib-cage of the animal and the darkened area are normal lung fields. They should be the same on both sides, but what we did with this animal was introduce the virus into this side, and you can see that it is not darkened, in fact it's very white. This is a classic depiction of an pneumonia, or inflammation into the part of a lung into which we placed the virus, and it would be serious definitely in the setting of a patient with cystic fibrosis whose lungs are otherwise compromised.NARRATOR:
And just 4 months later, the same kind of serious inflammation was observed in Ron Crystal's third patient.
RON CRYSTAL:
What happened was that about 12-24 hours after administration of the vector to the lung, our patient developed a fever began over a period of 2-3 days to develop some signs of consolidation or inflammation in the lung, in the region we had put the vector. We managed all this on the ward, there was no special intensive care unit, and the patient left the hospital absolutely on schedule. This was a mild to moderate adverse event in drug development, but it was not something that caused us enormous amount of alarm. It was alarm because we observed it and of course we were very concerned about our patient, make sure she was OK.BOB WILLIAMSON:
Under those circumstances you get worried first and foremost for the patient, as we know many of the people with cystic fibrosis and in the second place we were very worried that this was going to be a major setback for gene therapy. I mean if the patient had died obviously it would have been a terrible setback for the research.NARRATOR:
By mutual agreement between the scientific team and the US authorities, the trial was stopped, and Ron Crystal set about trying to discover how much damage the adenovirus treatment had done, and what he could do to get round it.As news came through that Crystal's trial had been suspended, the British team made their final preparations to begin, but at the last moment they realised they didn't know what effect liposomes alone would have on a normal nose.
DR ERIC ALTON:
This is just the liposome, the control vehicle, and this is the stuff that the gene is dissolved in and I'm not getting the gene, but I am getting the liposome to see whether that makes any difference to the nasal PD measurement or not.NARRATOR:
The nasal PD is an electrical measurement made in the nose which is different from normal people and those with cystic fibrosis. The gene therapy should bring the CF readings towards normal. Eric Alton is in fact a world leader on taking this kind of measurement.PETER MIDDLETON:
Looking for the best potential difference inside Eric's nose.NARRATOR:
Peter Middleton was the human face of the trial. It was his job to deal with all the patients.PETER MIDDLETON:
The very first time it goes in often makes your eyes water.JUDITH BUNTING:
Will you do this to all the patients in the trial too?PETER:
Yeah, they'll have it done about 9 or 10 times over 6 weeks, so they'll get very used to it having it done.ERIC ALTON:
And it's this that will determine whether the gene therapy has worked or not, electrically.NATASHA CAPLEN:
Bob wants the meeting at 3.30 as he said before, yeah, that was all that was about.PETER MIDDLETON:
Right. (OK) And I've told David and I've told Duncan, right. Could you ring 4384, thanks.NARRATOR:
With the new results in hand, the entire team was called from their work to make the big decision. Were they finally ready to go ahead?PETER MIDDLETON:
...the two groups, so hopefully if we can change this population up to somewhere round here then electrically we'd be happy that we've done something.MAN: Natasha, How much DNA would we have if we increased...
NATASHA CAPLEN:
Well that would be dependent on...MAN:
On how much we end up withNATASHA:
...on the dose (TALKING TOGETHER) how much we increase the dose. We could certainly do if we do the 9 with the amounts we have, we could go up to 600 micrograms in a further three patients.ERIC ALTON:
Per nostril.NATASHA:
Per nostril.ERIC:
Which is what we have ethical permission for as well.DUNCAN GEDDES:
Does anybody want to raise any other points at the moment?ERIC:
Does anyone have any lingering doubts about one nostril or two nostril treatment? Just like to dispel that. I mean it's got to be two nostrils, but does anybody...MAN: vGot to be two nostrils.
ERIC:
...but does anybody have, want to fight? You were right, it's got to be two nostrils.DUNCAN GEDDES:
Right, and I think we now have to get out of this room.There's more work to do.
NEWSREADER (ANNA FORD):
Doctors in Britain have begun their first full-scale trials of gene therapy to try to cure inherited diseases. They're concentrating on cystic fibrosis, which causes severe congestion of the lungs and affects...NARRATOR:
So this is gene therapy, the future of medicine, but it's not very glamorous.The fragile combination of DNA and liposome can't be carried very far, so the team were relegated to a dingy basement where a sterile preparation area was available next door to the treatment room.
PETER MIDDLETON:
Your first dose in this little sterile tube in there, and we just hold that there, as we went through before with the water.SEAN CONROY:
Thank you.NARRATOR:
The procedure itself was very simple: the patients took a few drops of medicine in a spray up their nose, every 15 minutes for 2½ hours.PETER MIDDLETON:
Right here's your next dose.NARRATOR:
The point of this trial was not to make the patients feel better. It was simply to see whether or not liposomes could carry the gene into living human cells and make any difference at all.SEAN CONROY:
That's it.PETER MIDDLETON:
Keep going, keep going, keep going, keep going. Big one, big one, keep going, keep going, keep going, keep going, keep going, keep going, wonderful...NARRATOR:
As part of the trial, volunteers had their general condition assessed every few days to make sure the treatment had no ill effects, but this was a double blind trial. Neither Peter nor Sean knew if he'd actually received the gene. Sean could have been squirting nothing up his nose but fat and water. The nasal PD was also measured on a regular basis. If Sean had received the gene, the flow of salt and water in his nose should have been partially restored, and the electrical measurements that Peter took after the trial would be different from before.DUNCAN GEDDES:
We have always thought that a double blinded control trial is the only way to do these forms of studies because we all of us have an enormous investment in the results, the patients have an enormous investment in the results and we cannot be certain that we won't bias the results as we go along. If you imagine what it's like sitting, as Pete Middleton has to do, making measurements from inside somebody's nose and having to choose exactly the right moment to make the measurement when he desperately wants a result, he must not know what's gone into that nose. If he knows that that was the real stuff he will, whether he means to or not, he'll bias the results, so we think that we can't make measurements honestly unless we are completely blinded to what people have had.RON CRYSTAL:
....over a period of time. So have we defined the limits in terms of Adenovirus at least that affect...NARRATOR:
The 1993 cystic fibrosis conference took place in Dallas. It was the first time that most researchers had heard Ron Crystal speak since the problems with patient number 3.RON CRYSTAL:
...of this type. Now there's been a variety of various rumours, media things and so on about patients in our trial. The rumours, I don't know where they all started, but I started getting about 6 weeks ago to 2 months ago calls from various reporters starting in Europe and then the United States about illness in our patients and then death to one of the patients, death two of the patients, death of three of the patients. I started really getting worried when they were asking me if I had died...NARRATOR:
In fact the problem came down to too much medicine. To deliver the highest dose of virus, the team had to drip a couple of spoonfuls of fluid into the patient's lung. It had trickled too far down and the highly sensitive air sacs had become inflamed. With the distance of time, Ron Crystal became quite bullish about what happened.RON CRYSTAL:
Everyone, everyone who develops cystic fibrosis dies. The average lifespan in the United States is 29 years, with all our sophisticated technology is 29 years, so we are looking at an individual that we're considering doing gene therapy who may be 23 years old, we know that that individual, on the average, will not survive more than 6 more years. When you put that in the context of developing new therapies, it's very, very important to realise that there may be some toxicities that we have to accept to be able to cure the disease.
PETER MIDDLETON:
Realistically when, you know in 1999 when this is all working wonderfully, we're actually going to be treating kids that are only 6 months old. Now if they've got a projected lifespan of 40 years then if 20 years from now they're all getting lymphomas of the kidneys or something like that from some nasty virus, then no-one's going to say thank you very much 'cos they would have lived to 20 years anyway. You have ethical problems that you have to weigh up a risk with a definite benefit and work out which you like and which you don't like, and that's why liposome is a possibility.NATASHA CAPLEN:
And yet the whole thing is totally complicated by the fact that we haven't a clue what any of the risks are anyway. They're all theoretical risks still at the moment anyway.SEAN CONROY:
When the gene therapy came along it gave me sort of a reassurance. Even though it's not actually a cure it will prevent me from getting any worse, the way my lungs are at the moment and how generally fit I am, I'm sure I could keep myself to live to a ripe old age. If it wasn't about I suppose I'd just have to knuckle on and just keep fighting it. It's almost as though now the gene therapy's coming along you can slow down and have a rest so to speak.NARRATOR:
In early 1994, the London team pressed on with the nose trial, this time testing the highest dose of gene. Meanwhile in New York, Ron Crystal and his team had restarted the lung trial, with a much lower dose of virus than before.MAN:
...cystic fibrosis and clearly have some good ciliate and bacteria cells there...NARRATOR:
They struck gold.MAN:
...as well as the neutrophils.MAN:
Right, it still leaves a lot of...RON CRYSTAL:
I realised that this therapy really was working in the sense of being able to transfer the gene and get that gene to function when I looked through the microscope and saw this picture, which is the cells from this individual that we had put the vector, this modified cold virus, down the lung and we were able to detect now the normal human cystic fibrosis protein where before it wasn't there.NARRATOR:
The staining showed that the missing gene had got into the lung cells of one of his patients and was working normally, but to cure the disease, the effect would have to be scaled up a million times and repeated at least once a month.DUNCAN GEDDES:
We're all going down, the lab team and the clinical team are going down to the meeting room downstairs to discuss the results of the trial and to break the code on the 15 patients that have been treated. The question is whether we've got enough to be encouraged by.PETER MIDDLETON:
Unfortunately absolutely nothing happens following 20 micrograms, or 200, and again 600 micrograms still nothing. Patient 4, he got 20 micrograms. I think basically nothing. Patient 10, who was the one that Natasha saw something interesting on PCR, as far as my electrics are concerned, absolutely nothing. The one that I was happiest with as having had the gene, was patient 15. He had a very nice response that was quite clear to measure and didn't have too much noise, and this looked quite real when he got 4½/5 millivolts on two occasions. I was happy that there was something changing there, but again still not up to normal.BOB WILLIAMSON:
Well we've got a safe procedure that doesn't work very well.DUNCAN GEDDES:
Do we think it works at all? What do you think Eric?ERIC ALTON:
I think the consensus must be that there are shreds of evidence that it is, that it's likely to be doing something, but I don't think we can say anything definite or clear-cut, but I think it's not an absolute zero ... I think..BOB:
This approach is safe right...I think our first results left us with the feeling of disappointment. It was only when we analysed them in detail and when we compared them with the fact that there were obviously quite serious problems with some of the other approaches, some of the viral approaches, that these also weren't giving really dramatic improvement in ion transport either, that we began to think hey, maybe this isn't quite so bad after all.
I think the major question which I would have is whether at this stage this is promising enough to consider a lung trial.
DUNCAN:
That's the key thing.BOB WILLIAMSON:
That's the critical issue.DUNCAN GEDDES:
Cos there's no question that this isn't efficient enough to be, yet to be... I want to go to the lungs quickly because that's where we want the treatment to work and I don't want to spend a lot of time perfecting a treatment with the nose which we don't ever want to use in the nose.BOB WILLIAMSON:
There's a big argument going on in the group, you know, I mean the group isn't certain. There are one or two people in the group who think we don't know enough yet, there are one or two people who think the only way we're going to find out is to do it. I suppose I'm sitting on the fence, I'm not by nature a fence sitter, but on this one I can see both sides.NARRATOR:
One of the leading geneticists in the country, Bob's reluctance to sit on the fence on any issue was notorious, and it soon became very public.NEWSREADER:
Crisis of confidence at London's teaching hospitals. Top professors quit over Health Service reform...BOB WILLIAMSON:
...here in London that the new system and the government policies have really made it almost impossible to carry out first-rate research here.As long as any project is research, it tends to be funded reasonably well and the real problem comes the minute it begins to change from being research into being something that we can offer to patients for treatment, and there's no way in which the very expensive early treatments are going to be covered by the National Health Service using the new financial mechanisms, so who is going to find the money for gene therapy for cystic fibrosis, who is going to find the money for any new initiative, and I must say that it breaks my heart to think that all of this research is going on and I can't see any clear way in which we're going to be able to offer it to patients as quickly as we should.
NARRATOR:
Bob Williamson was moving on, leaving London, the National Health Service and the gene therapy research programme.New Year, and the initial disappointment in London had turned to pride. The liposome had got the gene into enough cells to make a difference, and the team published their results.
NATASHA CAPLEN:
Relief, it's all over finally yes. No it's good to see it finally out. It's, it's a shame 'cos we're already thinking onto the next lot and what we're going to plan for the future, but it's very hard to actually completely commit and go over to that side until you've really closed that chapter and this represents that end of that part, you know, the data is out there for the rest of the world.NARRATOR:
The results showed that overall the gene had improved the electrical readings in their patients' noses by 20%. But what about Sean? Had he receivedthe gene, or did he just get fat and water?
SEAN CONROY:
A few hours after I actually took the medicine I did feel a lot clearer through my nose and sort of throat. Don't know if it's psychological, but it did feel better. It's almost as though you woke up on a spring morning and you could finally smell the flowers. But the next day when I actually went to the hospitalfor a PD, we'd run the usual test and it show, the figures had changed quite a lot for me. It wasn't sort of a drastic measure, but it had gone up sort of 4 or 5 points which was going towards a normal person.
PETER MIDDLETON:
Sean got 20 micrograms which was the lowest dose of the CF gene. I know he says that he felt better after having the gene, but he was the only one out of the 9 treated patients who actually did feel something, so maybe it means something, maybe it doesn't.DUNCAN GEDDES:
As with every trial of a new treatment you always ask for volunteers amongst the people who have the least to lose, which means we ask for the illest people, not those who were desperately ill at the time, but those who had the shortest life expectancy, but who were well enough to go through the trial, and inevitably that means that by now, some years afterwards, not everybody who took part in the trial is still alive. That is precisely the tragedy of cystic fibrosis - young men and young women dying in their early 20s, which is precisely why we're doing the trial.NARRATOR:
SEAN CONROY died after two severe bouts of pneumonia. He was just 21.MICHAEL CONROY:
He actually died on 18th May and he fought all the way up to the end. I couldn't have asked for him to have tried any more than he did for us. We were all there and we all loved him and pushed him and I don't even think at the end he actually gave up, I think it was literally his body gave out for him. We fought right the way through since his birth with the disease and for it to let him grow into manhood and then take him, and take him so quickly, is devastating.He was always one who was going to help with the treatment, all the new experiments
so it was never going to beat him, it was never going to beat him.
CHRISTINE SHAW:
I'm going to come back up in October, right?RON CRYSTAL:
That's correct.CHRISTINE:
And then...NARRATOR:
In New York the next step was to test repeat doses of the virus treatment. Christine Shaw was one of the early volunteers.RON CRYSTAL:
That's correct. You'll get the vector a total of 3 times. The first time will be on Tuesday, and then 3 months later, then 3 months after that.CHRISTINE SHAW:
I don't feel like I'm risking my health for this, but I feel like if anything I'm giving myself an opportunity to survive. I think that gene therapy is well, is my chance for survival, if it works in time, or if they discover how to make it all work in time.ALAN SMITH:
... The number of bases is right..NARRATOR:
But once again, animal studies were casting doubt on Ron Crystal's plans.Genzyme, an international biotech company, had been treating monkeys with repeat doses of the virus.
ALAN SMITH:
If we take an adenovirus and give it repeatedly to a monkey for example, we now know that that monkey will develop an antibody.That antibody has the property of neutralising the virus. Normally that would be a protective mechanism to stop the animal from getting a viral infection. In the case of gene therapy of course though what that means is that the neutralising antibody negates the effect of the incoming gene.
NARRATOR:
Genzyme's monkeys seemed to fight the doctored virus off as if it were just a bad cold. If the same thing happens in humans, the treatment will be worthless.DOCTOR:
...as you know sinus infections are very common in people with cystic fibrosis.RON CRYSTAL:
In the animal studies, whether it's studies in non-human primates - monkeys, or in mice or rats, the animals develop antibodies. You can detect those antibodies in the blood but it's possible that the humans will be different than the mice, rats and monkeys and we will be able to get that virus in. It's not a matter of, the immunity is only a problem for us for about 5 or 10 minutes when we administer the vector because our goal is here is the cell and it has a receptor on its surface for the virus, and here's the virus. It comes in and we've just got to get it to the cell. If we can do that before the immune system sees it, or if the immune system isn't as abundant or as vigorous in the human as it is in these animals against these viruses, then it's possible we can get away with it.NARRATOR:
Back in England, the London team had decided that their results were good enough to justify going into the lung. At this point it becomes an industrial process, and they chose to join forces with Genzyme.NATASHA CAPLEN:
What Genzyme has is facilities and people that they can commit to the very large scale production of this DNA. We're going to need to have about 100 times as much DNA for the lung trial because we need to get it everywhere in the lung and obviously that's a much larger surface area than just the nose and there's also personal connections: Alan Smith, who I'm going to meet today, has known Bob Williamson for many years. That always helps to see these things sort of flow much better.ALAN SMITH:
Natasha.NATASHA CAPLEN:
Hi, Alan.ALAN:
Good to see you.NATASHA:
Good to see you.ALAN:
Have a good trip down?NATASHA:
Yes I did...ALAN SMITH:
The market for a successful CF gene therapy is fairly easy to calculate. We know how many patients there are worldwide, and we know the likely costs of a treatment because we know how much treatment costs today, and in the United States for example, for the 30,000 patients there, it costs about $750 million to treat them. Remember treat them but not, not particularly successfully in the way we're thinking of in terms of gene therapy, so it's very reasonable I think to think of the market worldwide for a successful treatment as being somewhere between half and a billion dollars. So many different, so many different functions.NARRATOR:
Gene therapy is such a sound commercial proposition that Genzyme are playing both sides of the field, testing both viruses and liposomes.NATASHA CAPLEN:
...across the world, does it actually make...NARRATOR:
In the UK they have entered into an informal arrangement where they manufacture the DNA for the lung trial and the London team share the results. The cost to Genzyme: about half a million dollars.ALAN SMITH:
Natasha's come here today because in her lab she will be making DNA literally in glass bottles and she will probably be able to make something like 10 milligrams in a good prep. Now the question becomes how do you do that when you need to make more? Well one way would be to go to yet a bigger fermenter. We'll perhaps go to a 600 litre reactor. ....Probably have to build a factory, but by then we'll probably know that it's working, right, so... Have a look down there. That's pretty neat, hey.....NARRATOR:
But it's never that easy.DUNCAN GEDDES:
I would like to be in a position to say that we had already started the lung trial. We haven't yet and there are a number of reasons why. The production issues are that the DNA that we used to begin with, with the nose trial, is proving difficult to manufacture in large quantities.NARRATOR:
The DNA that the team had checked in the nose was difficult to manufacture in bulk, so they had to think again. There are other forms of DNA and other liposomes that should work, but if they changed any of the trial ingredients the authorities might ask them to do more safety trials, to go back into the nose.DUNCAN GEDDES:
We'd be much quicker second time round.JUDITH BUNTING:
You're putting a terribly brave face on it.DUNCAN GEDDES:
It would be devastating to have further delays, but I mean we have to remember that we're in this to try to get an effective treatment and the moment that the regulators say you have to go back to the beginning, if they say that, they would have a reason for saying it and if the overall considerations of safety say you have to go back, you have to go back.NARRATOR:
The complications suffered in these CF trials are typical of those faced by all gene therapies. As yet there is no gene therapy for any illness.DOCTOR:
OK, deep breath please.RON CRYSTAL:
The hard parts of it are things that you can't totally control and studying humans is different than studying mice and rats and rabbits and you can't just have everybody come in and do your study in. People have their personal lives and they can't necessarily be part of the studies at the time schedule that we would like. It takes time and I think that's frustrating for everybody that's involved.NATASHA CAPLEN:
I think we've come an awfully long way. We've actually done a clinical trial. We got out there and we did it and that's an achievement in its own right. There was a lot of people that thought we weren't going to be able to do this for 5 years when we first started down the road of talking about this, that this was far-fetched.ERIC ALTON:
...and has also found that if we're going to do the comparisons...DUNCAN GEDDES:
I think 2 years ago to be a liposome person was almost laughable in the eyes of some of the viral people. Now I don't think that there's any-body who would put money one way or the other as to which system will be the best.ERIC ALTON:
...do we make the decision when we've gone through all that or do we...DUNCAN GEDDES:
We've come an enormous way in understanding but if you're a patient with cystic fibrosis how far have we come? We've come very, very short distance. We are in a far better position to do it now than we were before. Before we were guessing. Now we know fairly well what the road is that we've got to travel down, so a huge advance from my point of view, pretty small step for somebody with CF unfortunately.
Credits Narrator JACK FORTUNE Horizon wishes to thank The Family of SEAN CONROY Federation of European Biochemical Societies Gene Therapy Advisory Committee Camera RICKIE GAULD TOM INGLE TIM HEALEY Sound DAMON OSBORNE STAN PHILLIPS TONY GLOSSOP Dubbing Mixer BOB JACKSON Film Editor RUSSELL REES Horizon Unit Manager SHIRLEY ESCOTT Executive Producer DEBORAH CADBURY Written and Produced by JUDITH BUNTING Editor JOHN LYNCH
Email: horizon@bbc.co.uk ©BBC
