Enhancing the expression of CFTR using antisense molecules against MicroRNA miR-145-5p

We read with great interest the article titled “MicroRNA-145 Antagonism Reverses TGF-b Inhibition of F508del CFTR Correction in Airway Epithelia” by Lutful Kabir and colleagues (1). In this paper, the authors demonstrate that miR-145 mediates TGF-b (transforming growth factor-b) inhibition of synthesis and function of CFTR (cystic fibrosis transmembrane conductance regulator) in cystic fibrosis (CF) airway epithelia. Interestingly, they found that antagonists of miR-145 were able to interrupt TGF-b signaling and restore F508del CFTR modulation. Therefore, they suggested that miR-145 targeting may provide a novel therapeutic opportunity to enhance the benefit of F508del CFTR correction in CF epithelia. In agreement with this, we have elsewhere published data supporting the use of miR-145 targeting in CF, based on an antisense peptide nucleic acid (PNA) to target miR-145-5p (PNAa145) and enhance expression of the CFTR gene, which we analyzed at mRNA (qRT-PCR) and protein (Western blotting) levels (2). In support of the conclusion by Lutful Kabir and colleagues, our data suggest the use of suitably delivered antisense molecules targeting miR-145-5p to enhance the expression of CFTR (2). With respect to a possible microRNA (miRNA)-based therapeutic option, one limitation is of course the presence of more than 300 CFTR gene disease-causing mutations (www.genet.sickkids.on.ca/cftr/) (3). Besides the CFTR mutation leading to the deletion of the phenylalanine in position 508 (F508del CFTR), accounting for 50–90% CF chromosomes, most CFcausing mutations are missense (42%), nonsense (10%), frameshift (15%), splicing (13%), in-frame deletion/insertion (2%), and promoter (0.5%) mutations, which are now operationally categorized in six classes of molecular defects of the CFTR protein (3).