Antisense Molecules Designed to Target SARS‐CoV‐2 are Nontoxic to the Host in a Murine Model
Authors: McCollum Colleen , Courtney Colleen , Aunins Thomas , O'Connor Nolan , Sharma Sadhana , Chatterjee Anushree 
Published: May 2022

The COVID‐19 pandemic has demonstrated the dire need for new treatment strategies against infectious disease. COVID‐19 has caused over 766,000 deaths in the United States. While multiple vaccines have been developed, the occurrence of new variant strains and the low rates of vaccination in some regions threaten the efficacy of these vaccines in keeping the global population safe. Current treatments for patients with severe COVID‐19 mainly focus on controlling the immune response or providing organ support, but while most patients recover from the disease, lasting effects may continue to disrupt patient lives and global fatalities remain high.

Here, we investigate the feasibility of using a novel antisense molecule as an antiviral against SARS‐CoV‐2. The antisense antiviral, called a nanoligomer, has been developed from Sachi Bioworks’ proprietary synthetic nucleic acid‐based drug discovery platform. The nanoligomers bind to specific DNA or mRNA sequences and offer high specificity and superior transport into cells. These molecules target the SARS‐CoV‐2 genome to prevent translation of the RNA‐dependent RNA polymerase ubiquitous in all RNA viruses, thus preventing viral replication. These antivirals were assessed for toxicity in mice using intranasal, intraperitoneal, and intravenous administration. Intranasal drug administration maximizes treatment concentration at the respiratory infection site, while intraperitoneal and intravenous administration gives further insight on biodistribution of the compound and responses in other organs.

Data shows a favorable safety profile in our murine model. Body weight of mice was unaffected by administration of nanoligomers. Serum parameters and organ histology indicated no changes compared to control mice. Cytokine levels remained largely below the level of detection, suggesting that the nanoligomers did not cause any inflammation or immune response in the mice. Further, biodistribution studies showed high initial bioavailability to the lungs, followed by rapid renal clearance and urinary excretion. The nanoligomers therefore show traits of being a safe therapeutic with favorable bioavailability and desirable clearance post‐treatment.

The antiviral presented is highly adaptable and the sequence may be adjusted to target new variants of respiratory viruses. The antisense sequence can additionally be designed to target a wide variety of DNA, mRNA, or miRNA, including host sequences linked to severe inflammatory responses to COVID‐19. A second nanoligomer we have designed and tested targets a human miRNA that has been shown to be upregulated in patients with severe symptoms in response to a SARS‐CoV‐2 infection. Binding this miRNA and preventing its action within the host may prevent damage to the host body caused by the immune response. The ability of these molecules to target either the virus itself or alleviate harmful host responses to infection makes nanoligomers a highly versatile treatment option for COVID‐19.