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Novel siRNA therapeutics demonstrate multi-variant efficacy against SARS-CoV-2

Ellen Bowden-Reid¹, Scott Ledger¹, Yuan Zhang¹

¹Kirby Institute, UNSW Sydney, Sydney, NSW, Australia.

Antiviral Research

|July 21, 2023

Abstract:

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a respiratory virus that causes COVID-19 disease, with an estimated global mortality of approximately 2%. While global response strategies, which are predominantly reliant on regular vaccinations, have shifted from zero COVID to living with COVID, there is a distinct lack of broad-spectrum direct acting antiviral therapies that maintain efficacy across evolving SARS-CoV-2 variants of concern. This is of most concern for immunocompromised and immunosuppressed individuals who lack robust immune responses following vaccination, and others at risk for severe COVID and long-COVID. RNA interference (RNAi) therapeutics induced by short interfering RNAs (siRNAs) offer a promising antiviral treatment option, with broad-spectrum antiviral capabilities unparalleled by current antiviral therapeutics and a high genetic barrier to antiviral escape. Here we describe novel siRNAs, targeting highly conserved regions of the SARS-CoV-1 and 2 genome of both human and animal species, with multi-variant antiviral potency against eight SARS-CoV-2 lineages - Ancestral VIC01, Alpha, Beta, Gamma, Delta, Zeta, Kappa and Omicron. Treatment with our siRNA resulted in significant protection against virus-mediated cell death in vitro, with >97% cell survival (P < 0.0001), and corresponding reductions of viral nucleocapsid RNA of up to 99.9% (P < 0.0001). When compared to antivirals; Sotrovimab and Remdesivir, the siRNAs demonstrated a more potent antiviral effect and similarly, when multiplexing siRNAs to target different viral regions simultaneously, an increased antiviral effect was observed compared to individual siRNA treatments (P < 0.0001). These results demonstrate the potential for a highly effective broad-spectrum direct acting antiviral against multiple SARS-CoV-2 variants, including variants resistant to antivirals and vaccine generated neutralizing antibodies.

Insights

Novel short interfering RNAs (siRNAs) show potent broad-spectrum antiviral activity against multiple SARS-CoV-2 variants, including resistant strains. These RNA interference therapeutics offer a promising direct-acting antiviral option for COVID-19 treatment.

Area of Science:

Virology
Molecular Biology
Drug Discovery

Background:

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes COVID-19, with limited broad-spectrum direct-acting antiviral therapies effective against emerging variants.
Immunocompromised individuals and those at risk for severe or long COVID require alternative treatment options beyond vaccination.
Short interfering RNA (siRNA) therapeutics present a promising avenue for broad-spectrum antiviral treatments with a high genetic barrier to resistance.

Purpose of the Study:

To develop and evaluate novel siRNAs targeting conserved regions of SARS-CoV-1 and SARS-CoV-2 genomes.
To assess the multi-variant antiviral potency of these siRNAs against various SARS-CoV-2 lineages.
To compare the efficacy of siRNA therapeutics against existing antivirals and evaluate multiplexed siRNA strategies.

Main Methods:

Design and synthesis of novel siRNAs targeting highly conserved genomic regions of SARS-CoV-1 and SARS-CoV-2.
In vitro testing of siRNA efficacy against multiple SARS-CoV-2 variants, measuring cell survival and viral RNA reduction.
Comparative analysis of siRNA antiviral activity against Sotrovimab and Remdesivir, and assessment of multiplexed siRNA efficacy.

Main Results:

siRNA treatment demonstrated significant protection against virus-mediated cell death (>97% cell survival) and reduced viral nucleocapsid RNA (up to 99.9%).
The developed siRNAs exhibited multi-variant antiviral potency against eight SARS-CoV-2 lineages, including Omicron.
siRNAs showed more potent antiviral effects compared to Sotrovimab and Remdesivir, with enhanced efficacy when multiplexed.

Conclusions:

Novel siRNAs targeting conserved viral genomic regions offer a highly effective broad-spectrum direct-acting antiviral strategy against multiple SARS-CoV-2 variants.
These siRNA therapeutics demonstrate potential for treating COVID-19, including infections with variants resistant to current antivirals and vaccines.
Multiplexing siRNAs can further enhance antiviral potency, highlighting their potential as a versatile therapeutic platform.

Read full analysis

Keywords:

Broad spectrum antiviral RNAi SARS-CoV-2 Variants of concern siRNA therapeutic

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