PA21259, SBIR Phase I, Developing a RIG-I agonist to prevent COVID-19

Project summary: Despite widespread availability of vaccines, the SARS-CoV-2 pandemic continues to wreak havoc on our healthcare system and our economy. High numbers of unvaccinated individuals combined with vaccine breakthrough cases continues to allow the virus to spread throughout the community and cause morbidity and mortality at high rates. There continues to be an urgent need for innovative therapeutics to address the current pandemic, as well as those which will inevitably arise in the future. Host-directed therapies (HDTs) offer a promising approach in this regard. Rather than targeting the virus itself, HDTs target the host to either restrict an essential growth factor or upregulate innate defenses. By targeting the host to attack the virus, traditional mechanisms of antiviral resistance are circumvented. We are developing a broad-spectrum antiviral RNA molecule targeting retinoic acid inducible gene-I (RIG-I), a host pattern recognition receptor (PRR) evolved to recognize viral RNA to trigger innate antiviral immune responses, an approach validated in preclinical studies to protect mice from multiple RNA and DNA viruses. Our preliminary data show the RIG-I agonist, PAMP105, prevents SARS-CoV-2 replication in vitro and can be effectively delivered to the lung to completely prevent disease from influenza and SARS-CoV-2 infection. In the proposed studies herein, we will perform critical formulation optimization to create a final product to be tested for efficacy against SARS- CoV-2 challenge in vitro and in vivo. We will optimize parameters of four clinically relevant nanoparticle formulations, including our novel nano-structured lipid carrier, which effectively protects and delivers RNA in vivo. We will optimize formulation parameters and downselect a final formulation by measuring cytokine release patterns in vivo from the blood, lung, and liver following innate immune agonist delivery. The lead formulated PAMP molecule will be tested for efficacy against a SARS-CoV-2 challenge in Syrian hamsters. To this point, little progress has been made clinically in developing innate immune agonists as therapeutics. Our expertise formulating agonists and vaccine platforms (including RNA) for preclinical and clinical trials will allow us to use a variety of nanoparticle formulations to deliver this RNA RIG-I agonist safely and effectively in a pressurized metered-dose inhaler to treat SARS-CoV-2 infection following exposure or after symptom onset. With results from this Phase I project, we will advance our formulated host-directed RNA molecule into clinical development as a as part of our Phase II research. Once developed, our therapeutic can be quickly pivoted for use against any number of current or emerging viruses, including influenza, Hepatitis B Virus, Hepatitis C Virus, Dengue Virus, or West Nile Virus, all of which are susceptible to PAMP in preclinical studies.