Non-CFTR-modulating therapies<< Back to Pre-clinical development
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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.
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 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
GSNO (S-nitrosoglutathione)3 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:
- 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
- In addition, they are also believed to attenuate inflammation and bronchodilation5 – and GSNO reductase inhibition has been shown to inhibit inflammatory mediators6