RNA Therapeutics for Treatment of Cardiovascular Diseases Promises and Challenges

Recent studies suggest that the majority of the human genome is transcribed, but only approximate to 2% account for protein coding exons. The remaining noncoding sequences include small noncoding RNAs, particularly microRNAs, which are approximate to 22 nucleotides in length. MicroRNAs posttranscriptionally control gene expression by targeting multiple mRNAs. By binding to the 3'UTR (untranslated region) of mRNAs, microRNAs induce degradation of the targeted mRNA or they block protein translation. Thereby, one microRNA is able to repress up to hundreds of genes in parallel. In addition to it, long noncoding RNAs (lncRNAs) with a length of >200 nucleotides comprise a more heterogenic class of noncoding RNAs that include, for example, intergenic lncRNAs, antisense transcripts, and enhancer RNAs. LncRNAs primarily act as epigenetic and transcriptional regulators but may also have additional functions as microRNA sponges or regulators of splicing. Finally, alternative splicing can lead to the formation of circular RNAs, which are highly stable RNAs that may act as microRNA sponges. Among the noncoding RNAs, many of them were described to control the cardiovascular system and may comprise novel therapeutic targets for the treatment of cardiovascular diseases. However, targeting coding RNAs is far more advanced in comparison to noncoding RNAs and has Food and Drug Agency-approved products. The tools to target coding mRNAs include different flavors of antisense oligonucleotides (ASO). Silencing can be achieved by morpholinos or GapmeRs with phosphothioate backbone linkages or silencing RNAs (siRNAs), which are double-stranded RNAs (approximate to 18-30 base pairs in length) that are chemically modified, for example, by 2'O-methyl nucleotides to increase stability and limit immunogenicity. Locked nucleic acids (LNAs) are RNA nucleotides with an extra bridge connecting the 2' oxygen and 4' carbon in the ribose sugar, which increases the melting temperature and, thereby, augments the efficiency (for summary, see Figure 1). Most clinical studies used such agents to target genes expressed in liver to either treat liver or metabolic diseases (for review, see Sehgal et al1). For example, siRNA-mediated silencing of PCSK9, an enzyme that regulates cholesterol transport and is highly expressed in liver tissue, was recently reported to efficiently reduce low-density lipoprotein cholesterol and was safely used in a phase I clinical trial. Thus, one may consider using these or other approaches also for targeting the noncoding genome.