Background

The current SARS-Cov-2 pandemic is enough evidence to realize the need for a broad-spectrum antiviral to provide protection against current and future viral outbreaks. The global economy has suffered each time due to several viral outbreaks over the last two decades, costing an estimated $70 billion in healthcare expenditures alone. SARS-Cov-2 pandemic has cost us millions of lives and a worldwide recession. These highlight the need for preparedness for unknown viruses. While there are some antiviral treatments available, they are super-specific to the virus such as Tamiflu for the treatment of influenza. They are also prone to fast resistance, given the mutational capacity of viruses. Unlike borad spectrum antibiotics, broad-spectrum antivirals do not exist. Thus we are also not prepared against new outbreaks.

Technology Overview

Researchers at Mount Sinai have identified a unique patient population having an ISG15 gene deficiency who show robust antiviral response against a multitude of viruses. These patients exhibit higher ISG expression. The select persistently overexpressed ISGs in isolation are the restriction factors for viruses; therefore, this population have natural protection against all strains of the viruses tested. Mount Sinai Researchers have validated this in dermal fibroblasts derived from ISG15-deficient patients and ISG15 knockout rhesus monkey and porcine cells.

The ISG15+ “normal” population, regulates interferon pathway and blocks the ISG expression. In these individuals, ISG15 stabilizes another molecule, USP18, which blocks the expression of ISGs. Providing modRNAs to which mimic ISG15 deficiency, and express select ISGs in healthy individuals via transient mRNA delivery could act as a broad-spectrum antiviral. Mount Sinai researchers demonstrated that the ISG modRNA cocktail reduced infection in cell lines challenged with multiple virus strains including SARS-Cov2.

Further Details

Qiu X, Taft J, Bogunovic D. Developing Broad-Spectrum Antivirals Using Porcine and Rhesus Macaque Models. J Infect Dis. 2020 Mar 2;221(6):890-894. doi: 10.1093/infdis/jiz549. PMID: 31637432; PMCID: PMC7050986.
Hermann M, Bogunovic D. ISG15: In Sickness and in Health. Trends Immunol. 2017 Feb;38(2):79-93. doi: 10.1016/j.it.2016.11.001. Epub 2016 Nov 22. PMID: 27887993.
Speer SD, Li Z, Buta S, Payelle-Brogard B, Qian L, Vigant F, Rubino E, Gardner TJ, Wedeking T, Hermann M, Duehr J, Sanal O, Tezcan I, Mansouri N, Tabarsi P, Mansouri D, Francois-Newton V, Daussy CF, Rodriguez MR, Lenschow DJ, Freiberg AN, Tortorella D, Piehler J, Lee B, García-Sastre A, Pellegrini S, Bogunovic D. ISG15 deficiency and increased viral resistance in humans but not mice. Nat Commun. 2016 May 19;7:11496. doi: 10.1038/ncomms11496. PMID: 27193971; PMCID: PMC4873964.

Stage of Development

Validated in vitro to prevent viral infection against SARS-Cov2, VSV, HSV1, ZIKA, Infleunza PR8 ( concept works in DNA and RNA viruses with either positive and negative strand, low and high path pathogenicity)
Optimizing modRNA cocktail
Future large animal validation

Benefits

Broad-spectrum antiviral against known or unknown viruses
Intranasal delivery
Host Mediated Therapy - Leverages the select parts of IFN-I signaling pathway to mimic ISG15 deficient patient population
Human genetic validation data – evidence of a safe treatment

Applications

Prophylactic treatment of known virus strains HIV, RVFV, HSV-1, IAV, SeV, Zika Virus, SARS-Cov-2
Prophylactic treatment of unknown virus strains

Modified RNA Cocktail of Interferon Stimulated Genes as a Broad-Spectrum Antiviral

Patents

IP Status