Friday, November 22, 2024
11/22/2024
Project summary: Despite the availability of a safe and effective vaccine, Hepatitis B virus (HBV) continues to be a major problem, chronically infecting ~300 million people worldwide and causing more than 500,000 deaths per year. 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. Current HBV therapies limit viral replication, but do not provide a cure for HBV infection. As such, there is an urgent need for innovative therapeutics to treat HBV infection and provide a lasting cure for infected individuals. 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, RAR, not only prevents HBV replication, but even clears cells of HBV DNA, something not achieved by any approved HBV treatments. In the proposed studies herein, we will perform critical formulation optimization to create a final product to be tested for efficacy against HBV infection. We will optimize parameters of two clinically relevant nanoparticle formulations, including our novel nanoparticle emulsion, which effectively protects and delivers RNA in vivo. We will optimize formulation parameters and down-select a final formulation by measuring cytokine release patterns in vivo from the liver, blood, and spleen following innate immune agonist delivery. The lead formulated RAR complexes will be tested for efficacy against HBV infection in vitro. 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 to chronically infected individuals. With results from this Phase I project, we will advance our formulated host- directed RNA molecule into preclinical development and in vivo efficacy studies as part of our Phase II research.
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