This page contains a Flash digital edition of a book.
Novel therapeutic approaches

thus quite unspecific to CFTR. High throughput screens have identified more CFTR-specific agents, called correctors, which are able to rescue and correct the trafficking defect of F508del-CFTR. The most successful one, so far, is the investigational drug VX-809/Lumacaftor. Nonetheless, and despite very promising results in primary and cultured cell lines,4

it promoted a

significant decrease only in sweat Cl- levels but no effect in the lung function in F508del homozygous patients during a Phase II clinical trial.5

Currently, VX-809 and VX-661 (a so-called second generation corrector) together with the potentiator VX-770 (see below) are in clinical trials. Interim results from phase II trial of VX-809 plus VX-770 showed improvement in lung function in patients homozygous for the F508del mutation.


Mutations in classes III and IV allow CFTR protein to be correctly localised but channel activity is either absent (class III) or reduced (class IV). CFTR potentiators such as genistein and other flavonoids can activate Cl-

conductance and thus

overcome these defects. The potentiator VX-770, named Ivacaftor/Kalydeco has been shown to increase CFTR activity in CF cells.6

When tested in CF patients

carrying the G551D mutation, it proved its efficacy in normalising sweat Cl- improving lung function.7

Soon after it

became the first approved drug to correct the basic defect of a CFTR-mutant. Moreover, when tested in CF cells, VX-770 has also been shown to correct other gating defect CFTR mutants,8


opening new avenues for the treatment of CF patients with these mutations.

Other agents: stabilisers, proteostasis regulators Class VI includes mutations leading to decreased stability of CFTR at the cell surface. Interestingly, when rescued to the plasma membrane by correctors, F508del-CFTR is also intrinsically unstable and thus it is also a class VI mutant. This can actually also account for limited success of the VX-809 corrector in clinical trials. We have recently shown that enhanced anchoring of F508del- CFTR at the cell surface, after rescuing by chemical correctors, with hepatocyte growth factor, boosts the modest restoration of its function up to 30% of wt channel levels in human airway epithelial



This finding indicates that surface anchoring and retention is a major target pathway for CF pharmacotherapy, namely, to achieve maximal restoration of F508del-CFTR in patients and in combination with correctors.

Bypassing CFTR

CFTR functions in the cell are not restricted to Cl-

can transport bicarbonate (HCO3-

transport. In fact, CFTR ) and

thus lack of CFTR leads to altered pH. Thus, while designing therapeutic strategies that correct the fluid and pH imbalance in CF, it is important to bear in mind that: (1) impairment of Cl-


HCO3- secretion through CFTR can be overcome by stimulation of non-CFTR anion channels/transporters thus leading to a balance in salt permeability, fluid and pH in epithelia; and (2) other dysfunctions besides the Cl-


secretion may also require an intervention. Pharmacological approaches aiming to correct several dysfunctions caused by the absence of CFTR, the so-called 'by-pass therapies',1 are discussed below.

Firstly, absence of CFTR at the apical membrane leads to enhanced Na+ conductance in surface airway epithelial cells, leading to excessive absorption of electrolytes.10

The responsible Na+

channel ENaC can be blocked by specific inhibitors such as amiloride, benzamil or phenamil and probably by activation of protein kinase C. Also, activation of purinergic receptors by ATP or UTP or denufosol inhibits ENaC.1

Secondly, stimulation of an alternative Cl-

channel, CaCCs, namely anoctamin 1 (ANO1 or TMEM16A), in CF airway epithelial cells by stimulation of luminal P2Y2 purinergic receptors with ATP or UTP, has been demonstrated to restore Cl-

secretion. luminal Cl- basolateral Ca2+

Thirdly, increasing of electrical driving of secretion by stimulation of the -activated K+

the benzimidazol compound 1-EBIO11 or

activation of cAMP-regulated K+ channels (KvLQT1) by agonists of the cAMP pathway, such as ß-adrenergic compounds1

blockers of phosphodiesterase like amrinone or milrinone can also be used to overcome CFTR dysfunction.1


Resulting from multiple efforts aimed at discovering drugs correcting the basic defect in CF, novel compounds modulating the mutant CFTR are coming

channel SK4 by or

to the final stages of clinical trials. The first CFTR modulator, Kalydeco, is now available to a small percentage of CF patients, that is, those bearing G551D. These novel compounds that reach the arrival line of the drug pipeline will hopefully very soon become available to a higher number of patients, with great expectations focused on the approval of a corrector for F508del-CFTR, the most common CF-causing mutation. Effective treatment of this life- threatening disorder will probably rely on a combinatorial approach using different drugs, each correcting the diverse basic defects of mutant CFTR. Until then, good pre-clinical assays and adequate trial endpoints are needed to bring these compounds to the clinical setting rapidly and efficiently. l

References 1. Amaral MD, Kunzelmann K Molecular targeting of CFTR as a therapeutic approach to cystic fibrosis, Trends Pharmacol Sci 2007;28:334–41.

2. Amaral MD, Farinha CM. Rescuing mutant CFTR: a multi-task approach to a better outcome in treating cystic fibrosis. Curr Pharmaceut Design 2013;19:3497–508.

3. Amaral MD. Therapy through chaperones: sense or antisense? Cystic fibrosis as a model disease, J Inherit Metab Dis 2006;29:477–87.

4. Van Goor F et al. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci USA 2011;108:18843–8.

5. Clancy JP et al. Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation. Thorax. 2012;67:12–18.

6. Van Goor F et al. Rescue of CF airway epithelial cell funtion in vitro by a CFTR potentiator, VX–770. Proc Natl Acad Sci USA 2006;106:18825–30.

7. Ramsey BW et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Eng J med 2011;365:1663–72.

8. Yu H et al. Ivacaftor potentiation of multiple CFTR channels with gating mutations. J Cystic Fibrosis 2012;11:237–45.

9. Moniz S et al. HGF stimulation of Rac1 signaling enhances pharmacological correction of the most prevalent cystic fibrosis mutant F508del-CFTR. ACS Chem Biol 2013;8:432–42.

10. Mall M et al. The amiloride-inhibitable Na+ conductance is reduced by the cystic fibrosis transmembrane conductance regulator in normal but not in cystic fibrosis airways. J Clin Invest 1998; 102:15–21.

11. Roth EK et al. The K+ channel opener 1-EBIO

potentiates residual function of mutant CFTR in rectal biopsies from cystic fibrosis patients. PLoS One 2011;6:e24445. 13

Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24