Future therapies

The Leeds Method of Management. April, 2008. Future Therapies [online]. Leeds Regional Adult and Paediatric Cystic Fibrosis Units, St James’s University Hospital, Leeds, UK. Available from http://www.cysticfibrosismedicine.com

Drug modulation of Cystic Fibrosis Transmembrane Conductance Regulator

The various CF mutations affect the function of the cystic fibrosis transmembrane conductance regulator (CFTR) in different ways. Some mutations result in abnormal CFTR production, whilst others affect the intracellular processing of CFTR, channel function, or a combination of more than one defect. Probably 5% to 10% functioning CFTR is required for a healthy life (Dorin et al, 1996). Various pharmacological approaches at correcting CFTR processing are being investigated. Certain mutations (Class 1 mutations, affecting about 10% of people with CF) have premature stop codons, which cause the production of either an abnormally short CFTR protein, or none at all. These mutations appear to be susceptible to drugs such as gentamicin, which can allow normal transcription (Hamilton2001). Gentamicin has been shown to successfully increase CFTR expression and function in a small clinical trial, but work needs to be done to reduce side effects (Clancy et al, 2001). An orally available and safe compound PTC124 is about to start phase III clinical studies for patients with this class of mutation.

People with the most common class 2 CF mutation, delta F508, could be helped by agents such as phenylbutyrate, which allow the delta F508 CFTR, which is normally retained and degraded within the cell, to reach the membrane where it can be expressed (Cheng et al, 1995). A clinical trial of phenylbutyrate has shown that it is safe and improves CFTR function as measured by nasal potential difference (Rubenstein & Zeitlin, 1998). A compound VX-770 is a so-called potentiator that acts on CFTR protein to open chloride channels, phase II studies have started to investigate its safety and pharmacokinetics.

Lastly, some CFTR mutants reach the cell membrane but have defective channel function (e.g. class 3 and 4 mutations). Drugs such as cyclopentylxanthine and the phosphodiesterase inhibitors have shown promise in improving the chloride conductance of such CFTR mutants in early clinical trials (Kelley et al, 1996; McCarty et al, 2002).

Ion transport modulation

As well as being a chloride channel, CFTR regulates the transport of other ions such as sodium (Boucher, 2002). It inhibits sodium transport across epithelial surfaces and is able to activate other types of chloride channel. Therefore, in CF the absorption of salt from the fluid lining the airways (called airway surface liquid) is increased. This leads to reduced airway surface liquid and to impaired function of the cilia clearing mucus from the lungs. Parion 55-02 is thought to correct the CF ion transport defects by acting primarily on abnormal sodium reabsorption. Phase I and phase II studies are complete and look promising.

New drug treatments currently under investigation in clinical trials to reduce salt absorption and thus maintain the volume of airway surface liquid in the lungs include Moli 1901 (Zeitlin et al, 2004), and INS 37217 (Deterding et al, 2005), which both function to improve chloride transport through channels other than CFTR.


CF is a very complex and chronic disease affecting almost every system in the body. As treatment is continually improved and developed, the outlook improves every year. We confidently expect today’s children with CF to live into middle age at least (Fredericksen et al, 1996; Dodge et al, 2007). The identification of the CF gene has brought the prospect of more effective and specific treatment (Ferrari et al, 2002).

There is no doubt that the prognosis will continue to improve until this more specific treatment becomes available (Dodge et al, 2007).


Boucher RC. An overview of the pathogenesis of cystic fibrosis lung disease. Adv Drug Deliv Rev 2002; 54:1359-1371. [PubMed]

Cheng SH, Fang SL, Zabner J, et al. Functional activation of the cystic fibrosis trafficking mutant delta F508-CFTR by overexpression. Am J Physiol 1995; 268: L615-L624. [PubMed]

Clancy JP, Bebok Z, Ruiz F, et al. Evidence that systemic gentamicin suppresses premature stop mutations in patients with cystic fibrosis. Am J Respir Crit Care Med 2001; 163: 1683-1692. [PubMed]

Deterding R, Retsch-Bogart G, Milgram L, et al. Safety and tolerability of denufosol tetrasodium inhalation solution, a novel P2Y2 receptor agonist: results of a phase 1/phase 2 multicenter study in mild to moderate cystic fibrosis. Pediatr Pulmonol. 2005; 39: 339-348. [PubMed]

Dodge JA, Lewis PA, Stanton M, et al. Cystic fibrosis mortality and survival in the UK: 1947-2003. Eur Respir J 2007; 29: 522-526. [PubMed]

Dorin JR, Farley R, Webb S, et al. A demonstration using mouse models that successful gene therapy for cystic fibrosis requires only partial gene correction. Gene Ther 1996; 3: 797-801. [PubMed]

Ferrari S, Farley R, Munkonge F, et al. Recombinant Sendai virus-mediated CFTR cDNA transfer. Paed Pulmonol 2002; Suppl 24: 221.

Ferrari S, Geddes DM, and Alton EW. Barriers to and new approaches for gene therapy and gene delivery in cystic fibrosis. Adv Drug Deliv Rev 2002; 54: 1373-1393. [PubMed]

Frederiksen B, Lanng S, Koch C, et al. Improved survival in the Danish centre treated cystic fibrosis patients: results of aggressive treatment. Pediatr Pulmonol 1996; 21: 153-158. [PubMed]

Hamilton JW. Gentamicin in pharmacogenetic approach to treatment of cystic fibrosis. Lancet 2001; 358: 2014-2016. [PubMed]

Kelley TJ, Al Nakkash L, Cotton CU, et al. Activation of endogenous DF508 cystic fibrosis transmembrane conductance regulator by phosphodiesterase inhibition. J Clin Invest 1996; 98: 513-520. [PubMed]

McCarty NA, Standaert TA, Teresi M, et al. A phase I randomised, multicentre trial of CPX in adult subjects with mild cystic fibrosis. Pediatr Pulmonol 2002; 33: 90-98. [PubMed]

Rubenstein RC, Zeitlin PL. A pilot clinical trial of oral sodium 4-phenylbutyrate (Buphenyl) in delta F508-homozygous cystic fibrosis patients: Partial restoration of nasal epithelial CFTR function. Am J Respir Crit Care Med 1998; 157: 484-490. [PubMed]

Zeitlin PL, Boyle MP, Guggino WB, et al. A phase I trial of intranasal Moli1901 for cystic fibrosis. Chest 2004; 125: 143-149. [PubMed]