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Ivacaftor: a quantum leap in treating cystic fibrosis?

In the second article of the series, Martin Hug outlines the development of ivacaftor and its major contribution to the treatment of cystic fibrosis

Martin J Hug PhD Pharmacy, University Medical Center Freiburg Freiburg, Germany Email:

Cystic fibrosis (CF) is an autosomal rec essive disorder characterised by highly viscous mucus that impairs the airway clearance, thereby paving the way to recurrent infections of the respiratory tract. Organs of the gastrointestinal tract, such as the small and large intestine, the bile duct and the pancreas, are also severely affected in most patients suffering from CF. The therapeutic mainstay so far has been merely symptomatic. Mucolytic agents such as N-acetylcysteine, osmolytes and recombinant DNAse are aimed to liquify the sticky mucus whereas oral, parenteral and inhaled antibiotics are used to treat the bacterial infection. Orally administered pancreatic enzyme preparations support the otherwise insufficient digestion of nutrients. These drugs are not able to cure the disease but the combination of these therapeutic regimens helps to increase the lifespan and decrease some of the burden of patients with CF.

Soon after the gene encoding the 20

cystic fibrosis transmembrane conductance regulator (CFTR) protein was discovered by positional cloning,1 hopes were raised that a cure for CF was nearby. Unfortunately, attempts to correct the genetic defect using viral and non-viral gene transfer vectors had been inconclusive and, in some cases, even potentially dangerous to the patients.2 Gene therapy has not been completely

“Gene therapy has not been abandoned completely but other strategies that are aimed at restoring CFTR function have evolved”

abandoned, but other strategies have evolved. The latter are either aimed to restore CFTR function or to bypass the defective protein entirely by activation of other anion channels.

Alternative anion channels Anion transport requires the concerted action of ion channels in combination with active and passive transporters. For decades scientists have been searching for epithelial anion channels that could complement the function of CFTR.

Because no other cAMP-dependent anion channel had been found as yet, most research has focused on channels that can be activated through elevation of the intracellular Ca2+


(CaCC). Recently, proteins such as the anoctamins (TMEM16) and bestrophins3 have been implicated to play a role in transepithelial ion transport. Most approaches to activate CaCCs are aimed at increasing intracellular Ca2+

via direct

or indirect mechanisms. Compounds that bind to P2YX2 receptors that are

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