Perspectives in MicroRNA Therapeutics for Cystic Fibrosis

Abstract

The discovery of the involvement of microRNAs (miRNAs) in cystic fibrosis (CF) has generated increasing interest in the past years, due to their possible employment as a novel class of drugs to be studied in pre-clinical settings of therapeutic protocols for cystic fibrosis. In this narrative review article, consider and comparatively evaluate published laboratory information of possible interest for the development of miRNA-based therapeutic protocols for cystic fibrosis. We consider miRNAs involved in the upregulation of CFTR, miRNAs involved in the inhibition of inflammation and, finally, miRNAs exhibiting antibacterial activity. We suggest that antago-miRNAs and ago-miRNAs (miRNA mimics) can be proposed for possible validation of therapeutic protocols in pre-clinical settings.

Keywords: CFTR; bacterial infection; cystic fibrosis; inflammation; miRNA therapeutics; microRNAs.

Figure 1

MicroRNA therapeutics. Picture created using Bio-Render.com (7 November 2024).

Figure 2

MicroRNA Therapeutics: the anti-miRNA approach. A forced inhibition of the miRNA activity can be obtained using antago-miRNA (anti-miRNA) oligonucleotides (AMOs) (e.g., DNA, RNA, and nucleic acids analogs such as LNA, PNA, 2′-MOE), delivered with vectors (A) or bioconjugated for an increased cellular uptake (e.g., R-PNAs) and/or a targeted delivery (B). MicroRNA inhibition can also be achieved using anti-miRNA sponge RNA sequences that contain multiple microRNA binding sites (C). The approach based on the use of zipper oligonucleotides is shown in panel (D) [31]. The binding between the miRNA and the anti-miRNA molecules leads to the inactivation of the miRNA, as it can no longer bind to its molecular target, i.e., messenger RNA, thus increasing protein production. Picture created using Bio-Render.com (7 November 2024).

Figure 3

MicroRNA therapeutics: the “miRNA-masking” approach. The down-regulation of microRNA functions is obtained through miRNA masking oligonucleotides and analogs delivered to cells (A,B), which act by masking the miRNAs binding site of target mRNAs through a direct hybridization of the miRNA “mask” with the 3′UTR region of mRNA. Created using Bio-Render.com (7 November 2024).

Figure 4

MicroRNA therapeutics: the “miRNA-replacement” approach. This strategy is based on the use of molecules (mature double-strand microRNA mimics or pre-miRNA oligonucleotides) that can restore physiological levels of miRNA with consequent inhibition of mRNA translation. Created using Bio-Render.com (7 November 2024).

Figure 5

Mechanism of action and molecular targets of miR-93-5p according to the reports published by Fabbri et al. [106], Xu et al. [109], and Gao et al. [111]. MicroRNA miR-93-5p directly interacts with IL-8 mRNA, thereby inhibiting IL-8 production and release [106]; in addition, miR-93-5p inhibits IRAK1, thereby preventing NF-kB activation and expression of NF-kB-dependent genes, such as IL-8 [109]; in addition, miR-93-5p is able to interact with TLR-4 mRNA [112], thereby down-regulating the NF-kB pathway.