Keeping hope alive

Boys with Duchenne muscular dystrophy face the devastating prospect of slowly wasting away, and then dying young. A revolutionary new gene therapy could change that

The consultant said nothing to the two parents. Instead, he passed a note across the table that contained three devastating lines: Muscle-wasting disease. Wheelchair by nine. Death by 16. "That was all it said," recalls Gail Fitzpatrick. "Basically, you feel as if your world has come to an end."

So their six-year-old son Josh was not flat-footed, for which one consultant had been treating him for three years. Instead, his problems with walking were due to a genetic, muscle-wasting disorder known as Duchenne muscular dystrophy (DMD), for which there is no cure. "We were given no hope," adds his father Paul Fitzpatrick, a fireman. "The consultant's attitude was: 'This child will be dead by 16 or 20. You had better get on with your lives and make the best of it.'"

That was four years ago, and since then the situation for parents faced with the shock of a diagnosis of DMD has been transformed, thanks in no small part to the energy and determination of the Fitzpatricks. From their home in Rotherham, they have run workshops and set up internet message boards where people can ask for help and support each other, as well as founding an organisation called Parent Project UK, dedicated to finding a viable treatment and cure.

Already, a treatment to repair the faulty gene is due to be put through a human clinical trial next year. "We have shown in mice that it is possible to patch up the gene so that it starts working again," says Professor Francesco Muntoni of Imperial College in London. "This is not a cure because you will have to keep repeating the treatment, but it may slow the loss of muscle."

DMD is caused by a mutation in the dystrophin gene that, nobody knows why, is huge - the largest in the body. It contains the information for making the protein dystrophin, which is vital for muscle function. Without it, all the muscles of the body, usually starting with those in the legs, gradually wither and die, to be replaced by fat. Vital muscles, such as those powering the heart and lungs, are also eventually affected. Because the gene is found on the X chromosome, it almost exclusively affects boys - one in every 3,500 births. Girls with two X chromosomes usually have a functioning version that they can use.

When the Fitzpatricks received the devastating news, the first thing they did was to look it up on the internet to find out all they could about DMD. "That made us realise that almost nobody we met knew anything about it," says Paul. "GPs might only see one case in their whole career, and other people would lump it together with multiple sclerosis or cystic fibrosis." Even the prognosis they were given was wrong, according to Professor Muntoni. "Today, the average age of death is 27, and there are many who live into their thirties," he says.

As a result of their research, the Fitzpatricks gained a sense of power. "We realised that the situation wasn't totally hopeless," says Paul. They found out about treatments that, although little used in this country, did seem to make a difference to patients' lives. For example, Canadian doctors were giving steroids to patients, and there were journal articles showing that they were effective. But then they faced a new problem. "We had to persuade the paediatrician to prescribe the steroids, but the research finally convinced him." The results have been dramatic. "Since Josh has been on them, his mobility is 10 times better. He was falling five or six times a day. Now it's about once a week."

Another treatment that has helped many sufferers is being put on a ventilator at night to help their weakened lungs to breath. "It keeps the fluid out of their lungs, so they have fewer hospital visits for lung infections," says Paul. Findings like these were passed on to other parents via the internet, where those with older children often help those who have just been diagnosed. "Families with DMD are no longer isolated and without hope," says Paul."I hate to think what it was like even 10 years ago. Now, the push for treatments comes from patients."

Some doctors are happy to work in partnership with empowered parents, but others find it more threatening. "We had one whose attitude was, 'I'm the consultant, I tell you what to do'. Because of this attitude, we still meet parents who believe that nothing can be done because that's what the paediatrician told them."

The lesson that emerges from this is that it is possible to create a life that works even with DMD. The Fitzpatricks wanted to keep things as normal as possible for Josh, and so felt it was vital that he stayed at the local school. "It has been marvellous," says Gail, who works at a call centre. "When he's in assembly, rather than being in his wheelchair he wants to sit on the floor with everyone else. But he can't get up. So at the end of assembly, the children around him just sit there and let him climb up them. It's fabulous."

In fact, although it is medical breakthroughs that tend to make the headlines, what can actually make a difference to the lives of people with DMD and other disabilities is often more mundane. Like adapting the house to the child's needs - £50,000 - or buying a van that can take a wheelchair - £8,000. On a disability grant of £300 a month, however, such life-enhancing changes can be impossible. "One of the major problems for families with DMD is not so much the muscular decline as having to spend their lives sorting out practicalities," says Professor Muntoni. "They become drained. Few have the guts and energy to do what those in the Parent Project are doing."

On trips to Scandinavia, Professor Muntoni sees a different picture. "I'm always struck by the quality of life of people with DMD there, simply because more money is available." Indeed, a recent British film, Inside I'm Dancing, centres on the struggles of two disabled young men, one with DMD, to lead independent lives.

In the face of these difficulties, one can but marvel at the courage and optimism of the Fitzpatricks and the other parents. "They say we'll have a medical breakthrough in the next five years," says Gail. "Josh will be 15 and full time in a wheelchair. A patch might not give him back the use of his legs, but if it keeps his heart and lungs working, and he can move his arms, he's got 90 per cent of his life back."

The most familiar approach to correcting a faulty gene is with gene therapy - inserting a working gene into the DNA using a modified virus. But not only has this method not been very successful, despite having had billions spent on it, but with DMD there is an additional problem. The gene is so huge that it is effectively impossible to cram it into a virus. So Professor Muntoni has developed what he calls a "molecular patch" that knits together parts of the gene that have been separated, and allows RNA in the muscle to "read" the faulty DNA, and so make some of the vital dystrophin. The muscles of mice with the damaged gene started producing dystrophin when injected with the "patch", technically known as an "RNA oligonucleotide".

But it's much harder correcting genetic problems in muscle than in other parts of the body, simply because there is so much of it. Also, it is not practical to inject every muscle. So the next step was to deliver the "patch" via a drip into the bloodstream. This has now been done with mice, and the fact that they naturally develop a condition almost identical to DMD increases the chance that it will work in humans. The next stage will be to test whether the injection has any serious side- effects in humans.

Professor Muntoni is optimistic. "Oligonucleotides have been used in cancer patients for years," he says, "and they are well tolerated." He believes that real improvement will come when two or three different treatments can be used together. "Possibly muscle stem cells and gene therapy and oligonucleotides. The tragedy is, however, that today's patients can't wait for very long."