Next RNA Therapeutics: The Mine of Non-Coding

Abstract

The growing knowledge on several classes of non-coding RNAs (ncRNAs) and their different functional roles has aroused great interest in the scientific community. Beyond the Central Dogma of Biology, it is clearly known that not all RNAs code for protein products, and they exert a broader repertoire of biological functions. As described in this review, ncRNAs participate in gene expression regulation both at transcriptional and post-transcriptional levels and represent critical elements driving and controlling pathophysiological processes in multicellular organisms. For this reason, in recent years, a great boost was given to ncRNA-based strategies with potential therapeutic abilities, and nowadays, the use of RNA molecules is experimentally validated and actually exploited in clinics to counteract several diseases. In this review, we summarize the principal classes of therapeutic ncRNA molecules that are potentially implied in disease onset and progression, which are already used in clinics or under clinical trials, highlighting the advantages and the need for a targeted therapeutic strategy design. Furthermore, we discuss the benefits and the limits of RNA therapeutics and the ongoing development of delivery strategies to limit the off-target effects and to increase the translational application.

Non Coding RNAs as Regulators of Wnt/β-Catenin and Hippo Pathways in Arrhythmogenic Cardiomyopathy

“…This stem-loop RNA is exported to the cytoplasm by exportin 5 and Ran-GTPase. Then, the pre-miRNA is processed by Dicer into a short double-strand molecule, which is recruited by the RISC complex in order to select one of the strands to interact with Argonaute proteins (Ago) and finally exert its function by targeting the 3′UTR of its target mRNA [ 36 , 37 , 38 , 44 , 45 ] ( Figure 6 ).…”

Noncoding RNAs Emerging as Drugs or Drug Targets: Their Chemical Modification, Bio-Conjugation and Intracellular Regulation

“…Ribozymes are RNA molecules with enzymatic activity. They bind to the target RNA and lead to RNA cleavage in a recycling manner [ 46 ] Ribozymes are composed of two domains: the recognizing region for target binding and the catalytic domain [ 47 ]. Ribozymes require a conserved target gene, which plays critical part in biological processes and accessible sterically for a smooth binding.…”

“…The simple structure, negligible toxicity, site-specific cleavage activity and recyclable catalytic potential of ribozymes benefit their effective modulation of gene expression. Several ribozymes have already been tested in clinical trials for solid tumors, HIV, SARS and other disease [ 45 , 47 ]. However, it is challenging due to the new mutations in the conserved target region and RNase degradation.…”

“…The CRISPR-Cas9 system as a DNA editing tool has been broadly used in genome modification for biology and therapeutic applications. In addition, a RNA editing CRISPR-Cas system, CRISPR-Cas13, has also been developed, which has a higher safety profile than CRISPR-Cas9 [ 47 ]. Recently, the CRISPR-Cas13-based system named PAC-MAN (prophylactic antiviral CRISPR in human cells) has been used in the treatment of SARS-CoV-2 [ 45 ].…”

Editorial: Non-coding RNAs in heart failure

“…That hypothetical primordial world has evolved into a dynamic modern perspective encompassing a plethora of noncoding RNAs that actively regulate information flow from DNA to proteins. We are still at an early stage in understanding the full depths of this process and the contributions of noncoding RNAs to diseases based on both experimental data and bioinformatics ( 2 , 3 ). However, this understanding could revolutionize the practice of medicine by offering novel molecular targets, as well as new therapeutic strategies.…”