miRNAs Offer Potential New Targets for Cystic Fibrosis Gene Therapy

A new study revealed that microRNA16 — a small non-coding RNA genes that regulates gene expression — can restore the F508del-CFTR protein function in airway cell lines and primary cultures of differentiated human bronchial epithelia from F508del homozygotes that express mutant CFTR protein endogenously. The finding is significant, as the F508del mutation is the most common one associated with CF. The study entitled “miR-16 rescues F508del-CFTR function in native cystic fibrosis epithelial cells” was published this July in Gene Therapy.

Cystic fibrosis (CF) is a hereditary disease that affects the lungs and digestive system, most frequently caused by a mutation in the cystic fibrosis gene known as F508del (though other gene mutations do exist). There is no cure for the disease and standard CF therapy up until recently has focused on controlling the symptoms. Unfortunately, most efforts to treat the underlying cause of the disease have failed in the past. To this point, cystic fibrosis is still not suitable for gene therapy due to its systemic nature and challenges including in vivo gene delivery and transient gene expression. MicroRNAs, however, may offer a new strategy for a genetic approach to treating the disease.

MicroRNAs (miRNAs) are short, 15-22 nucleotides, non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. Although the first human microRNA (miRNA) was discovered 10 years ago, therapeutic miRNAs have already entered Phase 2 clinical trials and are showing promise. There are two strategies in miRNA-based therapeutics: miRNA antagonists and miRNA mimics. miRNA antagonists function by inhibiting endogenous miRNAs that are highly expressed in diseased tissues while miRNA mimics work by restoring the function of a particular miRNA, also called “miRNA replacement therapy.”

In this study, the research team hypothesized that microRNA (miR)-based therapeutics could restore the dysfunctional outcomes of mutant CFTR — the underlying cause of cystic fibrosis. They reported that an miR-16 mimic could successfully restore F508del-CFTR protein function in airway cell lines and primary cultures of differentiated human bronchial epithelia from F508del homozygotes expressing the mutant CFTR. They also identified two additional miRs, miR-1 and miR-302a, also active. Normally, miR-16 is expressed at basal levels in CF and control cells while miR-1 and miR-302a are not detectable. They observed that the expression of miR mimics in CF lung or pancreatic cells significantly increased the expression of the F508del-CFTR protein. Notably, miR-16 promoted functional rescue of the cyclic AMP-activated apical F508del-CFTR chloride channel in primary lung epithelial cells from CF patients.

While traditional therapies for CF have only treated symptoms, a new wave of drugs are finally beginning to target and correct the genetic mutations that cause CFTR dysfunction. Most recently, the FDA’s approval of Vertex’s Orkambi medication offers cystic fibrosis patients with the F508del mutation a new treatment option that addresses the disease itself. Researchers hope that the findings of this study, which suggest that miR-16, miR-302a and miR-1 may constitute novel treatment targets for cystic fibrosis, could further contribute to the next generation of effective medications for the disease.