Of mice and men

May 14, 1999

Research into a genetic therapy to treat cystic fibrosis is moving ahead. Clare Sansom reports.

For centuries, German folklore has recognised that "the child will die soon, whose forehead tastes salty when kissed". Excessively salty sweat is still used as a diagnostic test for one of the most serious childhood diseases, cystic fibrosis.

CF is relatively common, affecting about one in 2,000 Caucasians; it is caused by a defect in a single gene, the cystic fibrosis transmembrane conductance regulator. This gene affects the transport of chloride and sodium ions, hence its link to excess salt. If it is absent, mucus builds up in many tissues, particularly the lungs, attracting bacterial infections. Modern medicine, particularly antibiotics and physiotherapy, has greatly improved the life chances of sufferers, but most still die from persistent lung infections in youth or early middle age.

Cystic fibrosis has become a "model" genetic disease. The inheritance pattern is simple, genetic tests are available and large numbers of affected individuals are keen to participate in trials aimed at developing new treatments. The CFTR gene was the first to be mapped from genetic information alone. A large, mainly United States-based research team, including a college student with CF, announced the discovery in Science magazine in 1989.

The technique used to discover the gene, linkage analysis, is now in routine use. But turning this knowledge into useful treatment is more difficult. For millions of people worldwide affected by serious genetic diseases such as CF, a cure by gene therapy is seen as a "holy grail". If a normal gene could be introduced into an affected person, it should be possible to reverse many genetic defects.

Advances in human genetics are staggering, with new genes being described each week. Yet progress towards clinically useful gene therapy remains agonisingly slow. Only very recently have results from clinical trials begun to show that genetic techniques may produce practical treatments.

David Porteous of the Medical Research Council's human genetics unit at Edinburgh University has been developing treatments for CF since before the gene was discovered. He explains: "Once we knew the basic defect we started thinking about how this could be exploited in new therapies. Cystic fibrosis is now relatively well controlled, and it is unethical to test experimental techniques on relatively fit young adults. That was one motivation for our developing an animal model of the disease."

Professor Porteous's group published a description of its mutant "CF mouse" just a month behind its American rivals. He says: "Both our mice and the US ones had defective CFTR genes, but there were important differences between them. The American mice usually died before weaning. Our mice lived into adulthood, showing mild signs of disease. This reflects the great variety seen in the human CF population."

The Edinburgh mice, which mimic a mild form of the disease, have the advantage that they live long enough to be used to test new treatments. Professor Porteous's group, and others in the United Kingdom, were soon able to demonstrate that transfer of the normal CFTR gene to nasal tissues of CF mice could restore some normal gene function.

The mouse is not an ideal model for human CF, as its lungs and other organs are so much smaller than those of humans. The Edinburgh group is collaborating with scientists at the Roslin Institute (famous as the creators of Dolly the sheep) to produce a sheep with the CF defect.

Experiments like this will always be controversial, but Andrew Blake, founder of the pressure group Seriously Ill for Medical Research, makes a strong case for them. "We, the seriously ill, are the ones on the front line of medical research. We would really lose if any biomedical research were halted."

Many groups are now developing ways to deliver the normal CFTR gene to human patients and restore its function. American and French workers have tended to use viruses to deliver the gene, while British groups have concentrated on synthetic delivery mechanisms. Both approaches have brought success, restoring up to 25 per cent of normal chloride transport in the nose. Now for the first time, a British-led group has shown that it is possible to deliver the gene to its real target: the lungs of patients with CF.

One of the principal investigators, Eric Alton of Imperial College London, says: "The results of this preliminary trial were very encouraging. About a quarter of the chloride transport in the lungs could be restored." Bacteria growing in mucus in the lungs cause much of the lung disease that eventually kills most CF patients. In early childhood, infections are usually easily controlled. Pseudomonas aeruginosa infection, which is common in later childhood, is more recalcitrant. After that, Professor Porteous explains, "Adult CF patients are often infected with a strange organism called Burkholderia cepacia. This, oddly, is normally a pathogen of onions: when it infects the lungs of CF patients it is very difficult to treat."

Back in the lab, studies suggest the bacterial burden can be reduced in patients treated with the CF gene. Although this progress is encouraging, it is impossible to predict when gene therapy for CF will be available on the National Health Service. Dr Alton explains that slow, steady progress is to be expected. "It normally takes about 10-12 years to get a drug from discovery to the clinic, and this one is no different from more conventional treatments. We have been going about six years and it is safe to say that we are still on track."

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