Associate editor: P. MolenaarNew pharmacological approaches for cystic fibrosis: Promises, progress, pitfalls
Section snippets
Cystic fibrosis — the disease in 2014
Cystic fibrosis (CF) is the most common life shortening condition in Caucasians and affects approximately 70,000 people around the globe including ~30,000 in North America and more than 30,000 in Europe (Sosnay et al., 2013). CF is an autosomal recessive disease which is caused by a mutation in each of the 2 CFTR genes.
So far, almost 2000 different mutations have been reported to the original CFTR mutation repository (www.CFTR.2.org, 214). F508del is by far the most common mutation. It is found
CFTR gene mutations and CFTR mutation classes
Generally, a higher frequency of the F508del mutation is observed in northern than southern European populations (Fig. 1A).
By comparison all other mutations are relatively rare. However, the relative frequency of specific CFTR mutations varies greatly between countries and even between regions within countries (Bobadilla et al., 2002), such is the case for G551D which also show heterogeneous geographic distribution (Fig. 1B).
In most countries, only 10 to 15 CFTR mutations occur at a frequency
The complex CF disease spectrum and the benefits of the CFTR2 project
Most of the nearly 2000 CFTR mutations described so far are likely pathogenic, since they are found in subjects with disease characteristics of CF. However, after the identification of the CFTR gene, an increasing number of CFTR mutations were described, also in subjects with milder disease characteristics such as isolated bronchiectasis and male infertility due to congenital bilateral absence of vas deferens (CBAVD). Data from CF newborn screening equally confirm the variability of the CF
Mutation-specific therapies or CFTR repairing therapies
Examining the molecular and cellular basis of CFTR mutations has also become important for designing effective treatments correcting the basic molecular and cellular defects, i.e., mutation-specific therapies (Amaral & Kunzelmann, 2007). Examples include (see Fig. 4):
- Class I:
Aminoglycoside antibiotics (e.g. gentamicin), and ataluren (PTC124) to some degree ‘over-read’ the premature termination codons thereby permitting translation to continue to the normal termination of the transcript (Wilschanski et
Pre-clinical assessment of CFTR-repairing molecules
Pre-clinical validation of novel compounds correcting CFTR in terms of their efficacy is required so that only the best candidates are trialled with patients. To this end investigational drugs should be tested ex vivo directly in native tissues from patients with CF or in cellular models with the rare mutations, towards a personalized-medicine approach.
Indeed, patients with CF begin to be in high demand for competing clinical trials. So far, efficacy testing on human bronchial epithelial (HBE)
CFTR by-pass therapies (ENaC, anoctamins)
The major virtue of these therapies is that they apply equally to all patients with CF. Whilst efforts proceed to identify novel correctors and to improve efficacy of correctors to rescue the most common defect F508del-CFTR, it is important to bear in mind that at least ~15% of all CF patients will not benefit from F508del-CFTR corrector therapy, as they lack F508del in both alleles.
Moreover, only ~40–50% % of patients are F508del-homozygous and efficacy of correctors on patients with only one
Impact of new treatments on the clinical course of CF, clinical practice and clinical decision making — perspective from the CF clinic
The potential for CFTR modulator therapy and other strategies that attack the basic CF defect has been a tremendous boost to the CF community and generally very positive for those giving and receiving care. Despite this, there are challenges beyond those posed by the complexity of CFTR dysfunction.
Conclusions
Since the discovery of the CFTR gene, the understanding of the complex biology of CFTR protein function has advanced significantly and allowed prospects of developments of therapies specifically designed to address the basic defects of CF. Several CFTR modulator therapies including ‘potentiators’, premature termination codon ‘read-through’ therapies and ‘correctors’ that underwent extensive in vitro evaluation are at present in late phase clinical trials. Ivacaftor, the first of these
Conflicts of interest
Scott Bell has participated and been supported to attend Investigator Meetings for Vertex Pharmaceuticals, has been a member of a Writing Group for manuscript preparation (combination ivacaftor/lumacaftor phase 2 study) and has been a site PI for a number of Vertex-sponsored trials. He has been supported to attend and to speak at Symposia (Gilead).
Kris De Boeck has served on advisory boards for Vertex, Ablynx, Aptalis, Galapagos, Gilead, Pharmaxis and PTC. She has been the principal
Permission
Fig. 1, Fig. 2, Fig. 3 have been reproduced and modified with permission of the publisher (De Boeck et al., 2014).
Acknowledgments
SCB is supported by a Queensland Health, Health Research Fellowship (QCOS013795). Work in the Bell Lab is supported by QCH Program Grant (#50005) and the TPCH Foundation (#MS2010-42). Work in the Amaral lab has been supported by strategic grants PEst-OE/BIA/UI4046/2011 (BioFIG) and FCT/MCTES PTDC/SAU-GMG/122299/2010 from FCT, Portugal, and CFF—Cystic Fibrosis Foundation, USA, Ref. 7207534.
The authors are grateful to Prof. Karl Kunzelmann (University of Regensburg, Germany) for the discussion
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