Development of a RIG-I agonist RNA as a cure for chronic Hepatitis B

项目总结： 尽管有安全有效的疫苗可用，但乙肝病毒(乙肝)仍然是一个主要问题， 每年导致全球约3亿人慢性感染，并导致50多万人死亡。高 未接种疫苗的人数加上疫苗突破病例的数量继续使病毒得以 在整个社区蔓延，并以很高的比率造成发病率和死亡率。目前乙肝病毒治疗的局限性 病毒复制，但不能治愈乙肝病毒感染。因此，迫切需要创新 治疗乙肝病毒感染并为感染者提供持久治疗的药物。 宿主导向疗法(HDTS)在这方面提供了一种很有前途的方法。而不是针对病毒本身， HDTS的目标是要么限制一种基本的生长因子，要么上调天生的防御能力。通过将目标对准 宿主攻击病毒时，传统的抗病毒耐药机制被规避。我们正在开发一种 针对宿主模式识别的视黄酸诱导基因I(RIG-I)的广谱抗病毒RNA分子 受体(PRR)进化为识别病毒RNA以触发先天抗病毒免疫反应的一种方法 在临床前研究中得到验证，可以保护小鼠免受多种RNA和DNA病毒的侵袭。我们的初步数据显示 RIG-I激动剂RAR不仅可以防止乙肝病毒的复制，甚至可以清除细胞中的HBVDNA， 不是任何经批准的乙肝治疗所能达到的效果。在这里提出的研究中，我们将执行关键的 配方优化，以创建最终产品，以测试其对乙肝病毒感染的疗效。我们将优化 两种临床相关纳米颗粒配方的参数，包括我们的新型纳米颗粒乳剂，它 在体内有效地保护和传递RNA。我们将优化配方参数并向下选择最终的 通过测量先天后肝、血和脾中细胞因子的体内释放模式来制定配方 免疫激动剂的输送。铅配制的RAR络合物将被测试对乙肝病毒感染的疗效 在试管中。 到目前为止，在开发天然免疫激动剂作为治疗药物方面，临床进展甚微。我们的 为临床前和临床试验制定激动剂和疫苗平台(包括RNA)的专业知识将使 美国将使用各种纳米制剂将这种RNA Rig-I激动剂安全有效地输送到 慢性感染者。根据第一阶段项目的结果，我们将推进我们制定的东道主- 将RNA分子引导到临床前开发和体内疗效研究，作为我们第二阶段研究的一部分。

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.