Lessons from SARS and MERS remind us of the possible therapeutic effects of implementing a siRNA strategy to target COVID‐19: Shoot the messenger

• Published in: Journal of Cellular and Molecular Medicine 2020-09, Vol.24 (17), p.10267-10269
• Main Authors: Habtemariam, Solomon, Berindan‐Neagoe, Ioana, Cismaru, Cosmin Andrei, Schaafsma, Dedmer, Nabavi, Seyed Fazel, Ghavami, Saeid, Banach, Maciej, Nabavi, Seyed Mohammad
• Format: Article
• Language: English
• Subjects: Animals; Antiviral Agents - pharmacology; Coronavirus Infections - genetics; Coronavirus Infections - therapy; Coronaviruses; COVID-19; COVID-19 - genetics; COVID-19 - therapy; Disease Models, Animal; DNA-directed RNA polymerase; Gene expression; Gene Expression Regulation, Viral; Gene silencing; Genetic Therapy - methods; Genome, Viral; Genomes; Hemorrhage; Hemorrhagic fever; Humans; Immune response; Infections; Innate immunity; Letter to the Editor; Macaca mulatta; Middle East respiratory syndrome; Open Reading Frames; Pathogenicity; Proteins; Replicase; Respiratory diseases; Respiratory syncytial virus; RNA polymerase; RNA, Small Interfering - pharmacology; RNA, Viral - genetics; SARS-CoV-2 - genetics; Severe Acute Respiratory Syndrome - genetics; Severe Acute Respiratory Syndrome - therapy; Severe acute respiratory syndrome coronavirus 2; siRNA; Spike Glycoprotein, Coronavirus - genetics; Transcription; Viruses
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.15652

The SARS‐COV‐2 as well as the SARS‐COV and MERS‐COV genomes contain several open‐reading frames (ORFs) that play an essential role in viral pathogenicity and infection.1-3 Based on previous experiences with other coronaviruses, ORFs are considered to be essential for viral replication through encoding viral replicase proteins to synthesize mRNAs of subgenomic length.1, 3 Silencing or small/short interfering RNA (siRNA) is a gene silencing approach using a small fragment of approximately 20‐25 base pairs of double‐stranded RNA that binds to a specific site of the relevant/target messenger RNA (mRNA); siRNAs are designed to silence genes at the post‐transcriptional level (by inducing cleavage and subsequent degradation of target mRNA) and can therefore be considered as vaccines or therapeutic agents. In 293 and HeLa cells, siRNAs targeting SARS‐CoV RNA‐dependent RNA polymerase (RDRP) showed therapeutic potential as well by specifically inhibiting RDRP expression.7 In addition, this system reduced plaque formation in Vero‐E6 cells, a cell line classically used to identify and count hemorrhagic fever viruses. An additional advantage of siRNA technology is the incredibly low dose required to eliminate SARS‐CoV infection; for example, less than 60 nmol/L in Vero E6 cells15 and 10‐40 mg/kg/daily in monkeys was sufficient for satisfactory therapeutic effects.5 The application and potential effectiveness of siRNAs have also been evaluated in MERS‐CoV using computational models.16 In view of angiotensin‐converting enzyme 2 (ACE2) as a recognized host cell receptor for the SARS‐CoV S protein, the development of siRNAs targeting key host proteins could hold promise. Despite their promising therapeutic effects, the application of higher doses of siRNAs, if so required, may be associated with some challenges, including adaptive18 and innate immune responses,19, 20 unwanted target effects, and saturation of the endogenous small RNA machinery.21 It is comforting, however, that previous data from several randomised, double‐blind, placebo‐controlled trials indicate that ALN‐RSV01 (a siRNA‐based drug) is safe to use and effective against respiratory syncytial virus infection.22, 23 Taken together, siRNA‐based therapeutics might be considered as an effective strategy to treat of COVID‐19.