Targeting MicroRNA Function in Respiratory Diseases: Mini-Review

Abstract

MicroRNAs (miRNAs) are small non-coding RNA molecules that modulate expression of the majority of genes by inhibiting protein translation. Growing literature has identified functional roles for miRNAs across a broad range of biological processes. As such, miRNAs are recognized as potential disease biomarkers and novel targets for therapies. While several miRNA-targeted therapies are currently in clinical trials (e.g., for the treatment of hepatitis C virus infection and cancer), no therapies have targeted miRNAs in respiratory diseases in the clinic. In this mini-review, we review the current knowledge on miRNA expression and function in respiratory diseases, intervention strategies to target miRNA function, and considerations specific to respiratory diseases. Altered miRNA expression profiles have been reported in a number of respiratory diseases, including asthma, chronic obstructive pulmonary disease, cystic fibrosis, and idiopathic pulmonary fibrosis. These include alterations in isolated lung tissue, as well as sputum, bronchoalveolar lavage fluids and peripheral blood or serum. The observed alterations in easily accessible body fluids (e.g., serum) have been proposed as new biomarkers that may inform disease diagnosis and patient management. In a subset of studies, miRNA-targeted interventions also improved disease outcomes, indicating functional roles for altered miRNA expression in disease pathogenesis. In fact, direct administration of miRNA-targeting molecules to the lung has yielded promising results in a number of animal models. The ability to directly administer compounds to the lung holds considerable promise and may limit potential off-target effects and side effects caused by the systemic administration required to treat other diseases.

Keywords: antagomir; microRNA; mimic; non-coding RNA; respiratory diseases.

Figure 1

MiRNA processing and function. The primary miRNA transcript (pri-miRNA) is transcribed from DNA and excised by Drosha, to produce the pre-miRNA. The pre-miRNA is exported to the cytoplasm by exportin-5 and spliced by Dicer to generate a miRNA duplex. The duplex is unwound by helicases and a mature single-stranded miRNA is assembled into the RISC complex. (A) MiRNA typically modulate target mRNA translation by complementary binding, within the 3′ UTR, 5′ UTR or coding region. New evidence suggests that miRNAs also function by (B) binding of DNA promoters, acting as RNA decoys or through direct binding of target mRNAs. (C) Mature miRNAs can also be released in exosomes and act on distant cells.