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Since the discovery of the gene encoding cystic fibrosis (CF), there has been much excitement about the possibility of gene therapy, which has now reached the stage of phase I clinical trials in adults. The baby born with CF has normal lungs at birth, but evidence of inflammation and lung changes are present as early as 4 weeks of age. Ideally, future novel treatments such as gene therapy should begin before the onset of airway damage. We review the pathophysiology of CF, including current molecular understanding, and set out the issues involved in gene therapy for children with CF.
Pathophysiology
CF is the commonest lethal inherited disease in white people in the UK, with an incidence of ∼ 1/2000 live births. The median estimated life expectancy of children born in the 1990s is 40 years, which represents a doubling in the past 20 years. It is estimated that in the next millennium half of all patients will be adults.
In 1989, the gene responsible for CF was localised to the long arm of chromosome 7. This gene encodes a protein called the CF transmembrane conductance regulator (CFTR), which is situated in the apical membrane of epithelial cells and functions as a chloride channel regulated by a cAMP dependent protein kinase. It also modulates the activity of other ion channels including the downregulation of the amiloride sensitive sodium channel.
More than 800 mutations of the gene have been identified and they are categorised into five classes on the basis of CFTR protein alterations. Class I mutations result in either unstable mRNA or an abnormal protein that is rapidly degraded. Class II mutations result in faulty processing of the protein and failure of the protein to traffic to the apical membrane. This class includes the ΔF508 mutation, which is a codon deletion resulting in …