RNA Therapeutics in Cardiovascular Precision Medicine

Abstract

Since our knowledge on structure and function of messenger RNA (mRNA) has expanded from merely being an intermediate molecule between DNA and proteins to the notion that RNA is a dynamic gene regulator that can be modified and edited, RNA has become a focus of interest into developing novel therapeutic schemes. Therapeutic modulation of RNA molecules by DNA- and RNA-based therapies has broadened the scope of therapeutic targets in infectious diseases, cancer, neurodegenerative diseases and most recently in cardiovascular diseases as well. Currently, antisense oligonucleotides (ASO), small interfering RNAs (siRNAs), and microRNAs are the most widely applied therapeutic strategies to target RNA molecules and regulate gene expression and protein production. However, a number of barriers have to be overcome including instability, inadequate binding affinity and delivery to the tissues, immunogenicity, and off-target toxicity in order for these agents to evolve into efficient drugs. As cardiovascular diseases remain the leading cause of mortality worldwide, a large number of clinical trials are under development investigating the safety and efficacy of RNA therapeutics in clinical conditions such as familial hypercholesterolemia, diabetes mellitus, hypertriglyceridemia, cardiac amyloidosis, and atrial fibrillation. In this review, we summarize the clinical trials of RNA-targeting therapies in cardiovascular disease and critically discuss the advances, the outcomes, the limitations and the future directions of RNA therapeutics in precision transcriptomic medicine.

Keywords: ASO; RNA therapy; antisense oligonucleotides; aptamer; cardiovascular precision medicine; microRNA; siRNA; silence interfering RNA.

Figure 1

RNA therapeutics in action. (A) Antisense oligonucleotides (ASOs); short, synthetic, single-stranded oligodeoxynucleotides that modify protein expression through the following mechanisms (Ai) Inhibition of protein production by antisense gapmers through activation of the ribonuclease RNAase H resulting in target mRNA degradation; (Aii) Control of splicing by ASOs in alternative splicing. ASOs can modulate alternative splicing by preventing the binding of splicing factors (SF) resulting in translational arrest through ribosome attachment blocking; (B) siRNAs. Double stranded (ds) RNA is processed by Dicer, a dsRNA-specific ribonuclease, into 21–25 nucleotide-long ds siRNAs with 2 nucleotides in their 3′ overhang and 5′ phosphate groups. siRNAs are then recognized by the Argonaute 2 (AGO2) and loaded into the RNA-induced silencing complex (RISC) and unwind into their single strand components. AGO2, which is a component of RISC, cleaves the sense strand of siRNA and the antisense strand binds with perfect complementarity to the target mRNA resulting in target mRNA cleavage; (C) microRNAs. Induction or inhibition of gene expression by microRNA mimics or inhibitors. (D) Aptamers. Aptamers are single-stranded DNA or RNA molecules selected through a large oligonucleotide library, called SELEX, to bind a specific target with high selectivity and specificity. Common targets include small metal ion and organic molecules, proteins, viruses, bacteria and whole cells. Target recognition and binding involve three dimensional, shape-dependent interactions as well as hydrophobic interactions. Here is a schematic illustration of the aptamer Pegaptanib inhibiting the action of the target protein VEGF-165 by binding to its receptor VEGFR.