Miracle of the drug that mends your faulty genes

Christine Falleti has spent much of her life combating the crippling effects of cystic fibrosis (CF).

Now 34, she is painfully aware that she’s approaching the age when most people with CF die.

Two friends with the disease already have.

But last year she took part in a test of a new drug that led to a dramatic improvement in her symptoms. Suddenly, she had a reason to hope her chances of dying might be reduced.

And it’s not just patients with CF who might benefit. The drug Christine was trialling is one of a new generation that could revolutionise the treatment of far more common diseases such as Alzheimer’s, cancer and diabetes.

For the first time, instead of treating the symptoms, it looks as if these drugs actually repair the effects of genes that cause disease.

CF affects 8,000 people in the UK and is caused by a mutation in just one gene, known as CTFR. It results in the patient’s lungs and gut becoming lined with thick mucus. Breathing can be difficult and digestion is poor because the extra mucus stops nutrients being properly absorbed.

Like many CF sufferers, Christine needs more than 15 medications every day to treat her symptoms. ‘It takes three hours to clear my airways,’ she says.

She uses a device like a life-jacket which, when inflated, vibrates her chest to shake the mucus free. Before going to bed, she does a dozen upside-down exercises while her partner slaps her upper back, sides and chest to loosen the phlegm.

Until now there haven’t been any drugs that can treat CF – or indeed any of the thousands of deadly conditions caused by a faulty gene, such as haemophilia and Huntington’s chorea. Doctors can only help patients deal with the symptoms. But that could change.

The drug Christine took, called VX-770, promises a revolution because it is able to reduce the damage caused by the mutation in the gene. The result was less mucus clogging up her lungs.

Within two weeks of starting the drug (as part of an American trial), she was breathing more easily.

‘I felt completely different,’ says Christine, a teacher from Ohio. ‘I could laugh without it turning into a five-minute coughing fit. Exercise became so much more enjoyable and easier.’

But once she stopped the drug after the four-week trial, her breathing was soon as bad as it had been before.

And that wasn’t the only downside. ‘It’s frustrating knowing there is something that can make you feel better but you can’t have it.’

There are three other similar drugs for treating CF being tested; again, these target the faulty genes rather than the symptoms.

Being able to correct errors in the CF gene means it should be possible to do the same thing for patients who have harmful mutations in other genes.

‘If these drugs fulfil their promise, it will be a major breakthrough,’ says Professor Kate Bushby, of the Institute of Human Genetics at Newcastle University, who has been involved in testing one of them.

CF has always been at the cutting edge of gene research. The CTFR gene was the first to be linked to a specific disease 20 years ago. ‘That discovery caused huge excitement,’ says Professor Bushby.

‘Everyone thought we’d start replacing the faulty genes with healthy ones prepared in the laboratory – genetic diseases would be history. But it proved much trickier than we thought.’

Putting the healthy genes into the cell came with side-effects. In some cases, the newly inserted genes were attacked by the patient’s own immune system. Even worse, in one trial, children given replacement genes developed leukaemia.

So rather than replacing these damaged genes, American scientists began searching for drugs that could repair them instead.

At the forefront of this was Dr Robert Beall, director of the American Cystic Fibrosis Foundation, who raised $175 million from various sources, including Microsoft founder Bill Gates’s charity.

The problem for CF patients is that their faulty gene affects a protein which is vital for transporting water in the airways and other passageways – this causes a lack of water, which is why their mucus is so thick.

Dr Beall and his team have identified two chemicals that can improve the way the protein works, and have turned them into two drugs (which could be used in combination).

The drug Christine was given boosts the effectiveness of the protein needed to transport water around the body.

The drug based on the other chemical works in a different way; it corrects a mistake in the way the protein is made. In most CF patients, this protein is slightly the wrong shape. The second new drug, VX-809, is able to tweak it back into shape.

This second drug opens up the possibility of treating other illnesses, such as Alzheimer’s and cancer, where again a protein hasn’t been made properly and is also slightly the wrong shape.

‘Poor protein folding is one of the main things that goes wrong when a gene becomes faulty in all sorts of other conditions,’ says Dr David Sheppard, a physiologist at the University of Bristol, who has been researching these two drugs. ‘What we need now is a large-scale trial to prove that benefits outweigh risks.’

One of the conditions the drugs might help with is male infertility. ‘It can be caused by thick mucus in the vas deferens, the tube that carries sperm to the penis,’ says Dr Sheppard. ‘Patients have a faulty CF gene, but no other symptoms.’

Around 10 per cent of CF sufferers have none of the water-carrying protein at all. They could be helped by a third drug, called Ataluren, which tricks the cells into ignoring the faulty gene’s message.

In an Israeli study of the drug, the rate at which CF patients coughed dropped dramatically. Someone with CF coughs around 650 times a day (a healthy rate is fewer than 16 times); on Ataluren, the coughing rate dropped to 450 a day.

Altaluren is being trialled in the UK as a possible treatment for Duchenne Muscular Dystrophy, the deadly muscle-wasting disorder for which there is no cure.

Meanwhile, Christine is keen to continue using the new drug. She says: ‘Every Monday, I call the clinic to see if I’m going to be put on to another longer trial with VX-770.

‘All I can do is cross my fingers and keep on with the other treatments, but none of them has the effect that VX-770 did.’

© 2009 Associated Newspapers Ltd.