CRISPR-based antiviral treatment of coronavirus infections

Unmet Need

The global market for antiviral drugs is a large one, topping $60B, and is getting larger due to the ongoing COVID-19 pandemic. Spurred on by a $3B investment from the U.S. government into antivirals development, companies such as Pfizer and Merck have developed new treatments for COVID-19 patients. These are important and effective lines of defense against SARS-CoV-2, but it is unclear how well they will work against current and future variants of the virus. Considering the proliferation of SARS-CoV-2 variants as well as the likelihood of future novel coronavirus outbreaks, there is a need for new antiviral strategies against coronaviruses.

Technology

Duke inventors with Ohio State University collaborator Dr. Yizhou Dong have developed an antiviral therapeutic system against coronaviruses. This approach uses a CRISPR-based system which, instead of editing the genome directly, cleaves transcribed RNA – effectively shutting down a gene's expression without lasting genome changes. Specifically, the inventors packaged CasRx mRNA and pre-gRNA oligo targeting the Ctsl gene, a host protease involved in the entry of coronaviruses into cells, into lipid nanoparticles that selectively target lung tissue. The gene therapy silences expression of the host factor Ctsl gene in lung tissue, which blocks the protein from helping the virus enter a cell. This therapy was demonstrated to be effective at inhibiting infection of mouse models by SARS-CoV-2.

Other Applications

This nanotherapy is applicable wherever transient knockdown of gene expression could have a therapeutic effect. For example, the inventors have also been able to inhibit expression of previously undruggable genes associated with castration-resistant prostate cancer in cell lines.

Advantages

• Demonstrated effectiveness on multiple variants of SARS-CoV-2, including Delta
• Ctsl gene is conserved as an important host factor for viral entry across coronaviruses, providing an attractive target
• Selective delivery to lung tissue
• Highly specific to Ctsl, sparing more important but genetically similar cathepsins
• Inhibits SARS-CoV-1 and -2 entry into both TMPRSS2-positive and -negative cells
• Transient effects do not create lasting edits to the genome
• Easily tweaked to target other host or viral factors required for infection by emerging coronaviruses and other threats