An intranasal ASO therapeutic targeting SARS-CoV-2.

Area of Science:

• Virology
• Molecular Biology
• Therapeutics

Background:

• The COVID-19 pandemic continues globally, driven by SARS-CoV-2 variants with increased infectivity and immune evasion.
• Current vaccination strategies may be less effective against emerging variants, necessitating alternative therapeutic approaches.

Purpose of the Study:

• To develop a novel, non-invasive therapeutic strategy targeting SARS-CoV-2 RNA to prevent or treat COVID-19.
• To evaluate the efficacy of locked nucleic acid antisense oligonucleotides (LNA ASOs) against SARS-CoV-2, including variants of concern.

Main Methods:

• Identification and design of an LNA ASO targeting a conserved 5' leader sequence stem-loop structure in SARS-CoV-2 RNA.
• In vitro testing of LNA ASO efficacy in preventing viral replication in human cells.
• In vivo testing of intranasal LNA ASO administration in a mouse model of COVID-19.

Main Results:

• The identified LNA ASO demonstrated nanomolar efficacy in inhibiting SARS-CoV-2 replication in human cells.
• Daily intranasal administration of the LNA ASO resulted in significant suppression of viral replication (>80-fold) in the lungs of infected mice.
• The LNA ASO was effective against all tested SARS-CoV-2 variants of concern in both in vitro and in vivo models.

Conclusions:

• Inhaled LNA ASOs targeting SARS-CoV-2 represent a promising therapeutic approach for reducing transmission and severity of COVID-19.
• LNA ASOs offer chemical stability and flexibility for targeting diverse viral RNA sequences, making them suitable for stockpiling against future coronavirus pandemics.