RNA Therapeutics in Cardiovascular Precision Medicine.

Ageliki Laina,Konstantinos Stellos,Georgios Georgiopoulos,Aikaterini Gatsiou,Kimon Stamatelopoulos

doi:10.3389/fphys.2018.00953

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.

Highlights

Cardiovascular disease (CVD) is the leading cause of death and disability in developed countries despite advances in risk stratification strategies and treatment (Benjamin et al, 2017)
We are witnessing tremendous advances in RNA therapeutics field and a rapid translation of experimental studies to human clinical trials paving the way toward precision medicine
There are challenges though to be overcome before RNA-based therapeutic agents could efficiently evolve into drugs

Summary

INTRODUCTION

Cardiovascular disease (CVD) is the leading cause of death and disability in developed countries despite advances in risk stratification strategies and treatment (Benjamin et al, 2017). To date only one miRNA therapeutic agent, miravirsen which is an LNA-modified DNA phosphorothioate ASO that inhibits miR-122, has been evaluated in a clinical trial (NCT01200420) in patients with chronic hepatitis C, showing prolonged dose-dependent decreased HCV RNA levels without serious adverse events (SAE) (Janssen et al, 2013). Volanesorsen is a second generation antisense oligonucleotide that has been designed to target APOCIII mRNA and is currently being evaluated in phase 3 clinical trials in patients with familial chylomicronemia syndrome (The APPROACH Study, The COMPASS Study) (Table 4). No changes in HDL-C were observed, while on the contrary significant reductions were established in apoB (38%), total cholesterol (26%) and Lp(a) (24%) (Cromwell et al, 2012) Along this line, another study evaluated the efficacy of mipomersen in patients with baseline LDL cholesterol levels>100 mg/dL with or at high risk for CHD already receiving maximally tolerated lipid-lowering therapy.

Study design

Findings

CONCLUSION AND FUTURE PERSPECTIVES