Since the discovery of the cystic fibrosis transmembrane conductance regulator gene in 1989, the promise of a targeted treatment for cystic fibrosis, the most common lethal genetic disease of Caucasians, has seemed within reach. The public and at least a generation of medical students heard the message that fixing the underlying defect, perhaps by gene therapy, would be "coming soon." Much of the early excitement for gene therapy has been tempered by the challenges of operationalizing the treatment approach for cystic fibrosis, as well as for other genetic diseases. At the same time, steady progress has been made in the fields of pulmonary care and nutrition to provide better support for cystic fibrosis patients. Although none of this progress addresses the damaged cystic fibrosis transmembrane conductance regulator (CFTR) ion channel protein, these general approaches extended the median survival of patients with cystic fibrosis from around 10 years to nearly 40 years, a remarkable accomplishment in spite of the absence of a "curative strategy."

In November, an exciting study was published that is sure to rekindle interest in and hope for targeting cystic fibrosis at the root of the problem (N. Engl. J. Med. 2011;365:1663-72).

Dr. Bonnie W. Ramsey of the Seattle Children’s Research Institute and colleagues conducted a randomized, double-blind, placebo-controlled trial to evaluate ivacaftor (VX-770), a CFTR potentiator, in patients with cystic fibrosis. The study is part of a growing field of work aimed at altering the pathogenic effects of genetically damaged proteins in genetic diseases. New drugs are being developed to bind to genetically mutated proteins to improve their functionality. While many are not expected to be complete cures, such medications could ultimately be added to the general supportive care applied to these conditions.

Since the CFTR gene discovery, hundreds of cystic fibrosis mutations have been identified, including G551D, which results in a protein that disrupts the ion channel function of the cystic fibrosis protein. Researchers speculated that it might be possible to find ways of "re-activating" the ion channel function of G551D and thereby recover some ion channel function and mitigate the severity of disease. Initial work of screening over 200,000 drug compounds identified ivacaftor, which showed promise as a potentiator for the ion channel for certain mutations. The strategy proposed was that ivacaftor could bind to the mutant cystic fibrosis ion channel protein and augment (or "potentiate") the damaged ion channel activity enough to recover enough "normal" ion channel function to reduce disease severity.

In the placebo-controlled study, 161 subjects received either ivacaftor or placebo and were followed primarily for the change in pulmonary forced expiratory volume in one second (FEV₁) after 6 months. In addition to a 10% greater improvement in FEV₁ in the treatment arm, ivacaftor-treated patients had less respiratory symptoms, fewer pulmonary exacerbations, and gained more weight as compared to the placebo group. Sweat chloride levels, still used to diagnose cystic fibrosis, also improved in the ivacaftor-treated group. Overall, the results are encouraging that this mutation-specific treatment holds promise for improving the medical outcomes in patients with cystic fibrosis. While this strategy would not work for all mutations, some studies suggest a modest effect with the most common "delF508" mutation. That mutation accounts for two-thirds of the mutations in Caucasian populations. Thus ivacaftor or similar drugs may be applied to additional CFTR mutations to help a larger subset of patients.