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Cystic fibrosis

Cystic fibrosis (CF) is an incurable genetic disorder that mainly affects the lungs and digestive system, and is the UK’s most common life threatening inherited disease. It affects about 1 in 2,000 children in the UK; five affected children are born and three patients die each weekANCHOR. Major improvements in treatment have increased average life expectancy to about 30 years from about four years in the 1950s. Nevertheless, quality of life is still severely affected.

Cause

Cause

CF is caused by a defect in the CFTR gene (identified in 1989), which makes a protein that transports salt and water in and out of the cells that line the lungs and gut. More than 1,200 disease-causing mutations are known to occur, some of which are more common than others. Depending on the exact type of mutation a CF child has inherited from their parents, the disease can be relatively mild or cause death in infancy.

Susceptibility to infection

Repeated lung infections and inflammation means that the average life expectancy for a cystic fibrosis sufferer is only 31 years – but improved treatments and the continued efforts of researchers mean that today’s CF babies may live well beyond this. Patients suffer repeated lung infections from various strains of the bacteria Pseudomonas aeruginosa and Burkholderia cepacia complex, which rarely cause problems in healthy people.

P. aeruginosa mutates in CF patients, changing its outer membrane and reducing the body’s defences. It may be possible to develop, using animals, a drug that blocks this mutationANCHOR ANCHOR. This susceptibility to infection is linked to low levels of lipoxin, tiny lipids that switch off infection-fighting white cells that accidentally damage the lung when fighting bacteria. Mice with damaged lungs infected with P. aeruginosa were able to fight off infection better when given lipoxin—which is related to aspirin and ibuprofen and explains why these drugs are beneficial to CF patientsANCHOR.

Cystic fibrosis mice

In 1992 four medical research teams in Britain and the USA bred mice with defects in their cystic fibrosis geneANCHOR ANCHOR ANCHOR ANCHOR. In 2004 a further strain was added; using this scientists were able to show that having enough liquid on airway surfaces is the key to preventing mucus build-up in the lungsANCHOR. This will be useful for testing lung treatments.

The underlying lung damage in CF is caused by high concentrations of salt, and the mechanism has been identified in CF mice as a defect in fluid transport. Several ways of correcting this have been developed in miceANCHOR.

Gene therapy

Animal experiments using CF mouse models has shown that it is possible to deliver a 'good' copy of the CFTR gene using liposomes to the lungs, which corrects the biochemical defect and restores normal lung functionANCHOR ANCHOR. These animal tests paved the way for clinical trials of non-viral gene therapy in the UKANCHOR ANCHOR ANCHOR ANCHOR ANCHOR which reported evidence of short-lived gene correction. These small trials in CF patients showed that the gene could be safely delivered to the cells lining the nose and that it has a positive effect on the underlying defect in the lungs. A shortened ‘minigene’ has been shown to be equally effective and easier to deliverANCHOR ANCHOR.

Now working together as a consortium backed by the Cystic Fibrosis Trust, three UK groups in London, Oxford and Edinburgh, have made substantial improvements to the gene therapy protocol. This has been tested in mice and sheep in preparation for further clinical trials. Fifteen CF volunteers are to join a single dose gene therapy trial in 2007, while a further 200 people are to be monitored. In 2008 up to 100 of these people will be recruited into a multi-dose gene therapy trialANCHOR ANCHOR.

Overcoming problems with CF gene therapy

Natural defences against allergens and irritants have made inhaled gene therapy hard to get into the lungs. Using a natural detergent-like substance called LPC, scientists have removed this resistance in mice. Animal testing has shown that the introduced gene and the benefit from it persisted for at least three months, which is as long as lung lining cells survive. This suggests that the gene had entered stem cells and been passed on with the stem cells' DNA when the cells divided. This may be a step towards overcoming the problems of human gene therapyANCHOR.

Fetal gene therapy

Research with adenovirus vectors using miceANCHOR, ratsANCHOR and primatesANCHOR has also shown that gene therapy in the womb may be more effective, while avoiding side effects.

Effects in the gut

In 2004 scientists found that treatment with oral curcumin, the yellow pigment of the spice turmeric, corrected the principal physiological defects associated with cystic fibrosis and prevented the gastrointestinal manifestations of the disease in miceANCHOR.


References

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