In the decade since the gene for cystic fibrosis (CF) was discovered, research into potential therapeutic interventions has progressed on a number of different fronts. The vast majority of morbidity and mortality in CF results from inflammation and infection of the airways. Direct delivery of antibacterials to the airway secretions via a nebuliser is an attractive therapeutic option, and a novel formulation of tobramycin designed for such a purpose has been demonstrated to improve spirometry and decrease the need for intravenous antibacterials. In addition, early clinical trials are studying the effects of small peptides with antibiotic properties (defensins) delivered directly to the airways.
Inflammation, whether secondary to infection or an independent feature of CF, leads to progressive bronchiectasis. Anti-inflammatories such as prednisone and possibly ibuprofen have been shown to decrease the rate of respiratory decline in patients with CF but have tolerability profiles that limit clinical usefulness. Macrolides also have anti-inflammatory properties and clinical trials are now ongoing to assess the efficacy of these agents in CF.
Multiple agents, including uridine triphosphate (UTP), genistein, phenylbutyrate and CPX (cyclopentyl dipropylxanthine), have been demonstrated in cell culture to at least partially correct the primary defect of ion transport related to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). No agent of this class has yet demonstrated clinical effectiveness, but several are in preclinical and early clinical trials.
Finally, gene therapy that allows for the incorporation and expression of wild-type CFTR in respiratory epithelial cells would be definitive therapy for CF. However, multiple barriers to delivery and expression need to be overcome. With research proceeding on these multiple fronts, new therapies for pulmonary complications romise to continue to increase the life expectancy of individuals with CF.
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Dr Aitken received research funding from targeted Genetics Corporation, Seattle.
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