Circular RNAs as Therapeutic Agents and Targets

Abstract

It has recently been reported that thousands of covalently linked circular RNAs (circRNAs) are expressed from human genomes. circRNAs emerge during RNA splicing. circRNAs are circularized in a reaction termed “backsplicing,” whereby the spliceosome fuses a splice donor site in a downstream exon to a splice acceptor site in an upstream exon. Although a young field of research, first studies indicate that backsplicing is not an erroneous reaction of the spliceosome. Instead, circRNAs are produced in cells with high cell-type specificity and can exert biologically meaningful and specific functions. These observations and the finding that circRNAs are stable against exonucleolytic decay are raising the question whether circRNAs may be relevant as therapeutic agents and targets. In this review, we start out with a short introduction into classification, biogenesis and general molecular mechanisms of circRNAs. We then describe reports, where manipulating circRNA abundance has been shown to have therapeutic value in animal disease models in vivo, with a focus on cardiovascular disease (CVD). Starting from existing approaches, we outline particular challenges and opportunities for future circRNA-based therapeutic approaches that exploit stability and molecular effector functions of native circRNAs. We end with considerations which designer functions could be engineered into artificial therapeutic circular RNAs.

CircMRPS35 suppresses gastric cancer progression via recruiting KAT7 to govern histone modification

“…At present, it has been reported that overexpression of native protective circRNAs can be achieved by lentiviral or adenoviral vectors in vivo. They will encode mini-gene cassettes with exon(s), as well as the endogenous splice donor and acceptor sites, and flanking intronic inverted repeats that support RNA backfolding [43]. For instance, microinjection of circDLGAP4 lentivirus significantly ameliorates ischemic stroke outcomes [44].…”

“…Moreover, the delivery of circRNAs follows the existing methods for delivering therapeutic linear RNAs, as no specialized possibilities or physicochemical obstructions have yet been found associated with circularity. The strategies contain systemic injection into the vasculature, subcutaneous injection or depots, or local application [43].…”

Circular RNA circRNF20 promotes breast cancer tumorigenesis and Warburg effect through miR-487a/HIF-1α/HK2

“…The 5' and 3' end of exon or intron are jointed to construct the closed loop. The alternative splicing for pre-mRNA transcript could yield diverse circRNAs subtype 10,11 . In human cancer, circRNA could diffusely modify the tumor progression by post-transcriptional regulation 12 .…”

Emerging Concepts and Challenges in Rheumatoid Arthritis Gene Therapy

“…Circular RNAs (circRNAs) are a novel class of transcribed RNAs found in Archaea [76] and a variety of eukaryotic organisms [77,78]. High-throughput RNA-sequencing has shown that at least 20% of currently active genes express circRNAs [79]. Usually, circRNAs are formed through "back-splicing" of the precursor messenger RNAs (pre-mRNAs), in which a downstream splice donor is joined to an upstream splice acceptor via a 3'→5' phosphodiester bond [80][81][82].…”

“…CircRNAs not only represent the possible targets for RA (see above) but also may be used as effectors targeting miRNA/siRNA [79]. CircRNAs are much more stable than mRNAs and may produce proteins.…”