tetano
Editor, Senior Moderator
Antiviral Res
. 2023 Jul 19;105677.
doi: 10.1016/j.antiviral.2023.105677. Online ahead of print. Novel siRNA therapeutics demonstrate multi-variant efficacy against SARS-CoV-2
Ellen Bowden-Reid[SUP] 1 [/SUP], Scott Ledger[SUP] 1 [/SUP], Yuan Zhang[SUP] 1 [/SUP], Francesca Di Giallonardo[SUP] 1 [/SUP], Anupriya Aggarwal[SUP] 1 [/SUP], Alberto Ospina Stella[SUP] 1 [/SUP], Anouschka Akerman[SUP] 1 [/SUP], Vanessa Milogiannakis[SUP] 1 [/SUP], Gregory Walker[SUP] 2 [/SUP], William Rawlinson[SUP] 3 [/SUP], Stuart Turville[SUP] 4 [/SUP], Anthony D Kelleher[SUP] 4 [/SUP], Chantelle Ahlenstiel[SUP] 5 [/SUP]
Affiliations
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.
. 2023 Jul 19;105677.
doi: 10.1016/j.antiviral.2023.105677. Online ahead of print. Novel siRNA therapeutics demonstrate multi-variant efficacy against SARS-CoV-2
Ellen Bowden-Reid[SUP] 1 [/SUP], Scott Ledger[SUP] 1 [/SUP], Yuan Zhang[SUP] 1 [/SUP], Francesca Di Giallonardo[SUP] 1 [/SUP], Anupriya Aggarwal[SUP] 1 [/SUP], Alberto Ospina Stella[SUP] 1 [/SUP], Anouschka Akerman[SUP] 1 [/SUP], Vanessa Milogiannakis[SUP] 1 [/SUP], Gregory Walker[SUP] 2 [/SUP], William Rawlinson[SUP] 3 [/SUP], Stuart Turville[SUP] 4 [/SUP], Anthony D Kelleher[SUP] 4 [/SUP], Chantelle Ahlenstiel[SUP] 5 [/SUP]
Affiliations
- PMID: 37478918
- DOI: 10.1016/j.antiviral.2023.105677
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.