Research on the development of multi-strain antiviral agents, modeled after exceptional immune system responses observed in a rare disorder

In a groundbreaking development, a team of researchers from Columbia University have created an mRNA-based antiviral system that shows broad activity against various viral pathogens, including Zika virus, SARS-CoV-2, and influenza. This breakthrough was published in the esteemed journal Science Translational Medicine in a paper titled "An mRNA-based broad-spectrum antiviral inspired by ISG15 deficiency protects against viral infections in vitro and in vivo."

The antiviral strategy developed by the team harnesses a suite of type I interferon (IFN-I)-stimulated genes (ISGs). Type I interferons are cytokines with potent antiviral and inflammatory capacities. The researchers engineered a system in which they reduced the ISG repertoire to a 10-ISG effector syndicate that effectively controls viral infection and severity of viral disease.

One of the key ISGs in this system is ISG15, which works to restrain the immune response to hold back inflammation. People with an immune disorder that lacks ISG15 have cells that can control a wide range of viral infections through a persistent, low-grade level of ISG expression. The team identified a collection of 10 ISGs that mimicked the broader antiviral activity of the interferon system and boosted cells' ability to resist Zika virus and SARS-CoV-2.

Expressing the set of 10 ISGs in an IFN-I-nonresponsive cell line increased cellular resistance to Zika virus, vesicular stomatitis virus, and SARS-CoV-2. The new antiviral was tested in live rodents, where it demonstrated protection against lethal doses of SARS-CoV-2 when given prophylactically. The same antiviral partially protected mice from influenza.

The work lays the foundation for a first-line, deployable antiviral platform that is virus agnostic and modular. Future work should focus on defining the minimal ISG combinations that still retain broad-spectrum efficacy and developing an RNA delivery mechanism for optimized RNA delivery and efficient, tissue-targeted expression.

The need for broad-spectrum antivirals has never been more pressing. Viruses are among the most serious threats to global health, and newer dangers such as SARS-CoV-2 have stressed the need for such treatments. Unfortunately, none of the 67 antiviral drugs currently approved by the U.S. Food and Drug Administration are clinically used as an effective broad-spectrum treatment for viral infections.

This new antiviral could inform the future development of broad-spectrum treatments or prophylactics for a range of viral pathogens. The authors responsible for the development of the new antiviral mRNA system reported in Science Translational Medicine are a research team from New York who designed a cocktail of ten modified mRNAs encoding interferon-stimulated genes (ISGs), known as modISG10. The platform could be developed into a versatile antiviral countermeasure, adaptable for rapid deployment against a wide range of viral threats.