Small molecule therapy

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 (Hamilton, 2001). 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.

Conclusion

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).

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