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Drug research and development » Pre-clinical development » Non-CFTR-modulating therapies

Non-CFTR-modulating therapies

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Non-CFTR-modulating therapies aim to restore CFTR function by modulating cellular components to restore ion transport or by introducing a new non-mutated copy of the CFTR gene to the cell.

Gene therapy

In contrast to molecular therapy which aims to correct the defects at protein level, gene therapy aims to treat the disease by inserting a gene into patients’ cells.1

So far, gene therapy has failed to demonstrate major clinical benefits for the treatment of CF. More research is required to improve the efficacy of gene therapy as it may represent an option to treat all patients with CF regardless of the mutation.2


CFTR by-pass therapies

CFTR by-pass therapies should be applicable to all patients with CF irrespective of the specific mutation, they would be the most widely applicable. The current approaches focus on normalisation of the ENaCs (sodium epithelial channels), which are hyperactive in the CF epithelia, or activation of alternative chloride ion channels (e.g. anoctamins).2

Small molecule inhibitors of S-nitrosoglutathione (GSNO) reductase

GSNO (S-nitrosoglutathione)levels are decreased in CF patients4,5 and restoring the levels improves F508del-CFTR in both in vitro and in vivo preclinical models.6 Through inhibition of the reductase enzyme, the primary catabolising enzyme for GSNO, these agents aim to increase GSNO levels.3 Small molecular inhibitors of GSNO may improve several aspects to CF:

  1. The inhibitors improve the function of the F508del CFTR7 – increase the amount of CFTR protein that reaches the cell membrane through stabilisation, prevention of proteasomal degradation and improvement of channel function4,6
  2. In addition, they are also believed to attenuate inflammation and bronchodilation5 – and GSNO reductase inhibition has been shown to inhibit inflammatory mediators6


  1. Quintana-Gallego E, Delgado-Pecellin I, Calero Acuna C. CFTR protein repair therapy in cystic fibrosis. Arch Bronconeumol 2014;50:146-50.
  2. Bell SC, De Boeck K, Amaral MD. New pharmacological approaches for cystic fibrosis: promises, progress, pitfalls. Pharmacol Ther 2015;145:19-34.
  3. Blonder JP, Mutka SC, Sun X, et al. Pharmacologic inhibition of S-nitrosoglutathione reductase protects against experimental asthma in BALB/c mice through attenuation of both bronchoconstriction and inflammation. BMC Pulm Med 2014;14:3.
  4. Cystic Fibrosis Foundation – Drug Pipeline. (Accessed October 2014, 2014, at
  5. Angers RC, Look Km, Mutka SC, Bove PF, Gabriel SE. Pharmacological Correction and Acute Inhibition of GSNOR Results in Improved In Vitro CFTR Function. In: 28th Annual North American Cystic Fibrosis Conference; 2014; Atlanta; 2014.
  6. Shoemaker S, Mandagere A, Troha J, Abbas V, Galloway C, Elhard M. Safety, Tolerability, and Pharmacokinetics of the Oral S-Nitrosoglutathione Reductase Inhibitor N91115: A Multiple Ascending-Dose Study In Healthy Subjects. In: 28th Annual North American Cystic Fibrosis Conference; 2014; Atlanta; 2014.
  7. Donaldson S, Taylor-Cousar J, Rosenbluth D, et al. Safety, Tolerability, and Pharmacokinetics of the Intravenous S-NitrosoglutathioneReductaseInhibitor N6022: An Ascending-Dose Study in Subjects Homozygous for the F508del-CFTRMutation. In: 28th Annual North American Cystic Fibrosis Conference; 2014; Atlanta; 2014.