Editors' ChoiceCystic Fibrosis

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Science Translational Medicine  11 May 2016:
Vol. 8, Issue 338, pp. 338ec74
DOI: 10.1126/scitranslmed.aaf9187

Up to a third of inherited genetic diseases and cancers may be due to premature termination codons (PTCs), and in many cases the phenotype is more severe compared with other types of mutations as there is complete loss of protein function. Efforts to promote translation through a PTC and thereby produce a full-length protein have yielded only a few compounds, most of which either have low efficacy or high toxicity.

PTCs account for 10% of cases of cystic fibrosis, a relatively common genetic disorder that is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) and primarily affects the lungs. In order to accelerate the discovery of safe drugs for this life-limiting disease, Mutyam et al. screened 1600 clinically approved compounds for their ability to increase read-through past CFTR PTCs. They used a high-throughput approach in cell lines to identify eight compounds that stimulated production of functional CFTR protein. Given that the United States Food and Drug Administration (FDA) recently approved ivacaftor, a potentiator of CFTR function at the cell surface, the authors also tested whether this therapeutic enhances the maximal effect of the lead compounds. Ivacaftor further increased the chloride current when added to all eight compounds in human airway epithelial cells derived from cystic fibrosis patients with either of two known PTCs in CFTR.

One promising candidate was escin, a widely used herbal compound from horse chestnut that is reportedly safe and effective for the treatment of chronic venous insufficiency. Escin topped the list in PTC suppression and functional enhancement. Although the ability of escin and ivacaftor to restore CFTR current to almost 50% of that in wild-type CFTR is impressive, optimal dosing, mode of delivery, and potential clinical benefit are notable unknowns. Nonetheless, the approach used here to screen clinically approved molecules can be a model for diseases other than cystic fibrosis.

V. Mutyam et al., Discovery of clinically approved agents that promote suppression of CFTR nonsense mutations. Am. J. Respir. Crit. Care Med. 10.1164/rccm.201601-0154OC (2016). [Abstract]

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