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

Ellen Bowden-Reid; Scott Ledger; Yuan Zhang; Francesca Di Giallonardo; Anupriya Aggarwal; Alberto Ospina Stella; Anouschka Akerman; Vanessa Milogiannakis; Gregory Walker; William Rawlinson; Stuart Turville; Anthony D Kelleher; Chantelle Ahlenstiel

doi:10.1016/j.antiviral.2023.105677

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

Antiviral Res. 2023 Sep:217:105677. doi: 10.1016/j.antiviral.2023.105677. Epub 2023 Jul 20.

Affiliations

¹ Kirby Institute, UNSW Sydney, Sydney, NSW, Australia.
² New South Wales Health Pathology, Sydney, NSW, Australia.
³ New South Wales Health Pathology, Sydney, NSW, Australia; Virology Research Laboratory, Serology and Virology Division (SAViD), Prince of Wales Hospital, Sydney, NSW, Australia.
⁴ Kirby Institute, UNSW Sydney, Sydney, NSW, Australia; RNA Institute, UNSW Sydney, Sydney, NSW, Australia.
⁵ Kirby Institute, UNSW Sydney, Sydney, NSW, Australia; RNA Institute, UNSW Sydney, Sydney, NSW, Australia. Electronic address: cahlenstiel@kirby.unsw.edu.au.

PMID: 37478918
DOI: 10.1016/j.antiviral.2023.105677

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.

Keywords: Broad spectrum antiviral; RNAi; SARS-CoV-2; Variants of concern; siRNA therapeutic.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Neutralizing / therapeutic use
Antibodies, Viral
Antiviral Agents / pharmacology
Antiviral Agents / therapeutic use
COVID-19* / therapy
Hepatitis C, Chronic*
Humans
Post-Acute COVID-19 Syndrome
RNA, Small Interfering / genetics
SARS-CoV-2 / genetics
Spike Glycoprotein, Coronavirus

Substances

RNA, Small Interfering
Antiviral Agents
Antibodies, Neutralizing
Antibodies, Viral
Spike Glycoprotein, Coronavirus
spike protein, SARS-CoV-2

Supplementary concepts

SARS-CoV-2 variants