This website is intended for healthcare professionals only.

Hospital Healthcare Europe
Hospital Healthcare Europe

Treatment of the basic defect in cystic fibrosis

Anne Munck
15 June, 2011  

Dr Anne Munck,
Paediatric Cystic Fibrosis Department,
University Hospital Robert Debre, APHP, Paris, France

Cystic fibrosis (CF) is the most frequent Caucasian life-shortening autosomal recessive disease. Current treatments for lung disease that target the consequences of CF transmembrane conductance regulator (CFTR) dysfunction have dramatically improved life expectancy. At present, in well-developed countries, CF is no longer a paediatric disease, since 
close to 50% of patients are adults.1 However, lung disease remains a major contributor to morbidity and mortality and, as yet, there is no cure for CF.

Since the discovery in 1989 of the gene responsible for CF,2 research fields have expanded rapidly, leading to improved understanding of the physiopathology of this complex multi-organ disease, and triggering the development of various animal models, and new potential therapies using compounds that counteract the underlying pathology. This review briefly describes the pathogenesis of lung disease and the different classes of CFTR mutations. It summarises recent therapeutic advances in gene therapy and CFTR modulation in the era of respiratory care.3-7

Pathogenesis of lung disease
The CF gene defect leads to an abnormal CFTR protein, which results in modified transmembrane conductance, with increased Na+ absorption and defective Cl- secretion at the apical membrane of the lung’s epithelial cells, causing surface liquid depletion in the airways and subsequent defective mucociliary clearance. The consequences of this combine mucus impaction, inflammation and chronic infection (mainly with Staphylococcus aureus and Pseudomonas aeruginosa) create a vicious circle resulting in progressive pulmonary deterioration.3,4

The CF gene is located on chromosome 7, and over 1,500 different mutations have been identified (database, although the number of CF-causing mutations appears much lower.8 The most common mutation F508 del, accounts for approximately 70% of all mutant alleles; depending on the ethnic background of the patient, less than ten mutations have a frequency of more than 1%.9

Mutations have been grouped into six classes10 according to their impact on the CFTR protein, ranging from absence of synthesis to malfunctioning. CFTR may be non-synthesized (class I, stop codon), inadequately folded (class II, e.g. F508del), or a full-length CFTR may be synthesized but not regulated (class III, e.g. G551D), with reduced conductivity of the ion channel (class IV, e.g. R117H), with transcription dysregulation (class V, splicing mutations) or accelerated degradation (class VI).

Classes I, II and III are most common and, when combined, they result in a classic CF phenotype – although a highly variable lung phenotype – while classes IV, V and VI are usually associated with milder pulmonary involvement. Thus far, however, the prognosis of genetic mutation is of limited clinical value, since the impact of gene modifiers and environmental factors is of utmost importance in the phenotypic severity of lung disease.11 On the other hand, classification of CFTR mutations highlights a new therapeutic approach, with treatment strategies targeted at specifically repairing the mutant protein.

Gene therapy
Since the discovery of the gene, CF has been considered a promising candidate for gene therapy.12 It is a monogenic disease. Chloride transport was restored, both in vitro in human nasal cells and in vivo in animal models and humans, by small amounts of functional CFTR. However, we do not yet know the extent of improvement in CFTR function that would make a clinical difference.13

Over the last 15 years, at least 25 phase 1/2 clinical trials involving more than 400 patients have been carried out using a variety of viral and non-viral gene transfer vectors. Many of those studies7 confirmed the proof-of-principle for airway gene transfer, but, until now, only a transient effect on CFTR expression could be observed.

Adenoviruses and adeno-associated virus (AAV) vectors seem to be more efficient than non-viral vectors, though they are more likely to induce a host-specific immune response after repeated dosing. An AAV-CFTR phase 2b trial demonstrated a good safety profile in 100 patients, but failed after repeated administration to statistically improve its primary efficacy endpoint in lung function.14 Overall, the use of adenoviruses has decreased dramatically over the last five years due to the problem of repeated administration which could not be overcome.

Lentiviral vectors15 may enable very prolonged expression of the transgene for the lifetime of the cell and can be repeatedly administered in mouse models; it is an active candidate for gene therapy and is under development by the UK CF Gene Therapy Consortium created in 2002 and by DNAVEC Corp (Japan). The potential risk of insertional mutagenesis in humans by this self-inactivating lentiviral vectors needs to be fully assessed in preclinical studies.

Clinical trials using non-viral vectors have shown only partial correction of chloride transport in nasal and lung epithelium, but are more likely to be repeatedly administered. The UK CF Gene Therapy Consortium has identified an attractive efficient gene transfer agent with refined plasmid DNA under the control of an optimised promoter with prolonged activity, complexed to the cationic lipid GL67A.16 A multidose clinical trial in approximately 100 subjects is currently under way; it will run for a 12-month period and it aimed at assessing whether non-viral therapy has a significant impact on clinically relevant pulmonary endpoints.

Mutation-specific and chloride channel pharmacotherapy
An alternative strategy to gene therapy lies in a therapeutic approach that targets the basic ion channel defect, with the aim of reducing severity or slowing the progression of the disease. These new molecules, now in various stages of development, focus on class-specific mutations and are therefore limited to patient subgroups. They are ‘CFTR modulators’, either ‘correctors’ of the mutated CFTR function or ‘potentiators’ that improve the chloride channel gating.

These potentially active agents, discovered by traditional or ‘high-throughput screening’ (HTS) strategies,16 have been identified and analysed, resulting in several new and promising compounds. This era is expanding rapidly with ongoing clinical trials.

Class I mutations with a premature termination codon
For class I mutations with a premature termination codon (PTC) resulting in a truncated non-functional protein, agents which enable read-through of a stop codon result in a full-length protein, thus restoring protein function. Topical nasal application or the intravenous route of aminoglycoside demonstrated improved CFTR 
function,18-19 but the aminoside concentration required for achieving chloride transport was not suitable for clinical use because of potential renal and ototoxicity.

A recently identified novel chemical compound issued from HTS strategy, PTC124 (Ataluren, PTC Therapeutics Inc, South Plainfield, New Jersey, USA) is an orally bioavailable agent that selectively induces ribosomal read-through of PTC. It enables protein translation to continue up until the normal end of mRNA transcription. The efficacy of this approach has been demonstrated in other diseases such as Duchenne’s muscular dystrophy and Hurler’s syndrome. In CF, in vivo efficacy in animal models has been demonstrated. Clinical trials in healthy volunteers, and currently in CF adults and children with at least one stop codon mutation, have shown rescue of CFTR activity in phase 2 studies assessed by the nasal potential difference (NPD).20, 21 A one-year randomised, blinded, placebo-controlled phase 3 trial in patients aged six years and older is currently ongoing in the USA and Europe, with an open-label 12-month extension period.

Identifying ‘potentators’ of mutant CFTR
Another exciting approach lies in identifying ‘potentiators’ of mutant CFTR, restoring endogenous regulation and ion transport. CFTR potentiators are agents that increase the ion channel activity of the CFTR protein located at the cell surface. They might also benefit patients bearing mutations other than those of classes III, IV and V, e.g. when combined with a ‘corrector’ agent in patients with class II mutations.

Flavonoids were among the first agents studied, but genistein demonstrated limited efficacy22 and poor developmental potential for inhaled and intravenous development.

Preliminary results with a new orally administered investigational CFTR potentiator VX 770 (Vertex Pharmaceuticals, Cambridge, Massachusetts, USA)23 look very promising. A phase 2, randomised, double-blind, placebo-controlled study in patients with at least one G551D mutation primarily evaluated safety, but also efficacy and pharmacokinetics.24 Dose-dependent improvements in CFTR-chloride conductance measured by NPD and in sweat chloride values were significant, and were associated with an increase in lung function over a four-week period.

Those data led to a large phase 3 randomised, double-blind, placebo-controlled one-year programme in adults and children aged six and older, which is currently ongoing in the USA, Europe and Australia with an open-label 12-month extension period. A phase 2 randomised, blinded, placebo-controlled study using this potentiator in multiple doses in patients over 12 years of age and homozygous for F508del is just now being completed.

Other potential drug candidates
Other potential drug candidates are directed toward ‘correcting’ the folding of F508del CFTR, thus improving trafficking and preventing further protein degradation. Among them, several small molecules have demonstrated controversial effects. They include: Sildenafil (Viagra), a phosphodiesterase-5 inhibitor acting in vitro as a F508del trafficking enhancer;25 Sodium-4-phenylbutyrate (PBA), disrupting normal histone interaction in the reticulum endoplasmic quality control system, possibly preventing mutant CFTR degradation;  and VX 325 a quinazoline compound26 which plays a chaperone role.

Two potential compounds might prevent the degradation of F508del CFTR via calcium disruption of the interaction between F508delCFTR and calnexin. For one of them, curcumin results are controversial.27 For the other, an alpha-glucosidase inhibitor28 called miglustat (Zavesca) – an orphan drug used to treat Gaucher’s disease, a phase 2 trial will begin in France by the end of this year.

Very recently, an orally available investigational F508CFTR corrector named VX-809 aimed at improving trafficking of the defective CFTR protein, has been evaluated with promising results, in a phase 2a randomised, double-blinded, placebo-controlled trial with four doses administered during a 28-day period.29 The primary endpoint was the evaluation of safety and tolerability. VX-809 was well tolerated across the dose groups.Moreover, statistically significant changes in sweat chloride, a secondary endpoint, were observed at day 28, with a clear dose response, suggesting an increase in F508CFTR activity in patients during dosing. The trial was not powerful enough to demonstrate statistical differences concerning the following parameters: nasal potential difference, F508CFTR maturation in rectal biopsies and FEV1. Results support future evaluation of VX-809.

In October 2010, Vertex initiated a phase 2a multiple-dose combination trial of VX-809 with the CFTR potentiator VX-770, in patients with the most common CFTR mutation, F508del. That clinical study will evaluate the safety and tolerability of multiple combinations of VX 770 and VX 809, as well as the effect on sweat chloride ( In vitro preliminary studies demonstrated additive effects when compared to dosing of VX-809 or of VX-770 doses as a single agent. Additive or synergistic rescue of F508del CFTR using more than one pathway may be the correct strategy for achieving adequate ion transport activity and thus a normal phenotype in CF respiratory and other epithelia.30

The CF community has shown strong interest in these new approaches. However, our currently available surrogate endpoints and biomarkers fail to show sufficient accuracy for rapidly identifying changes, thus allowing small patient numbers for clinical trials. Much work is going on to identify ideal parameters suitable to determine the success of gene therapy and small-molecule drugs. By improving communication between CF centre teams and CF patients concerning ongoing pre- and clinical trials, we hope to increase motivation and enthusiasm for further recruitment. In order to attain the ultimate goal, a cure for the disease, clinical trials will require major resources and strong commitment on the part of CF teams and patients.


  1. McCormick J et al. Lancet 2010;375:1007-13
Riordan JR et al. Science 1989;245:1066-73
Proesmans M et al. Eur J Pediatr 2008;167:839-49
Ratjen F. Respiratory Care 2009;54:595-605
Sloane P et al. Curr Opin Pulm Med 2010;16:1-7
Mogayzel PJ et al. Am J Respi Crit Care Med 2010;181:539-44
Griesenbach U. Expert Rev Resp Med 2009;3:363-71
Castellani C et al. J Cyst Fibros 2008;7:179-96
Claustres M et al. Hum Mutat 2000;16:143-56
Rowe SM t al. N Engl J Med 2005;352:1992-2001
Cutting RG. Hum Mutat 2009;30:1093-103
Kerem E. Curr Opin Pulm Med 2004;10:547-52
Alton E et al. Am J Respir Crit Care Med 2007;175:750-1
Moss RB et al. Hum Gene Ther 2007;18:726-32
Sinn PL et al. J Virol 2008;2:10684-92
  16. Hyde SC et al. Nat Biotechol 2008;26:549-        51
Galietta IV et al. Am J Cell Physiol 2001;281:1734-42
Wilchanski M et al. N Engl J Med 2003;349:1433-41
Sermet-Gaudelus I et al. BMC Med 2007;5:5
Kerem E et al. Lancet 2008;372:719-27
Sermet-Gaudelus I et al. Am J Respir Crit Care Med 2010; Jul 9 [Epub ahead of print]
Pyle LC et al. A J Resp Cell Mol Biol 2009 [Epub ahead of print]
Van Goor F et al. Proc Natl Acad Sci USA 2009;106:18825-30
Accurso F et al. N Engl J Med 2010;363:1991-2003
Dormer RL et al. Thorax 2005;60:55-9
Loo TW et al. Mol Pharm 2005;2:407-13
Mall M et al. Bioessays 2005;27:9-13
Antigny F et al. Cell Calcium 2008; 43:175-83
Clancey JP et al. J Cystic Fibros 2010. 33rd European Cystic Fibrosis Conference. S21[73]
Pedemonte N et al. Am J Physiol Cell Physiol 2010;298:C866-74