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

开发 RIG-I 激动剂 RNA 来治疗慢性乙型肝炎

• 批准号: 10699796
• 负责人: Bryan Berube
• 金额: $ 27.52万
• 依托单位: HDT BIO CORPORATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-14 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10699796
• 关键词: Adjuvant; Agonist; Antiviral Agents; Antiviral Response; Antiviral resistance; Bacterial Infections; Binding; Biodistribution; Blood; Blood Circulation; Cells; Cessation of life; Chronic; Chronic Hepatitis B; Clear Cell; Clinic; Clinical; Clinical Trials; Communities; Complement; Complex; DNA Viruses; Data; Dedications; Defensins; Development; Dose; Emulsions; Epidemiology; Event; Formulation; Gene Expression; Genes; Goals; Growth Factor; Hepatitis B Vaccines; Hepatitis B Virus; Hepatitis C virus; Hepatocyte; Human; Immune; Immune response; In Vitro; Individual; Innate Immune Response; Interferons; Intravenous; Investigation; Kinetics; Lead; Leadership; Legal patent; Licensing; Liver; Measures; Mediating; Molecular; Morbidity - disease rate; Mus; Natural Immunity; Nucleotides; Outcome; Pathway interactions; Pattern; Pattern recognition receptor; Peptides; Persons; Phase; Production; RNA; RNA Viruses; Reagent; Research; Resistance; Signal Transduction; Spleen; Testing; Therapeutic; Transfection; Translating; Tretinoin; Vaccines; Viral; Viral Load result; Virus; Virus Diseases; Virus Replication; adaptive immune response; anti-hepatitis B; antimicrobial; clinically relevant; cytokine; efficacy evaluation; efficacy study; efficacy testing; experience; immune activation; in vivo; innovation; microbial products; mortality; nanoparticle; novel; novel therapeutics; pathogen; preclinical development; preclinical study; preclinical trial; prevent; product development; programs; receptor; response; sound; targeted treatment; therapeutic target; transcription factor; unvaccinated; vaccine platform; viral DNA; viral RNA

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.

项目概要： 尽管已经有了安全有效的疫苗，乙型肝炎病毒（HBV）仍然是一个主要问题， 慢性感染全世界约 3 亿人，每年造成超过 50 万人死亡。高的 未接种疫苗的人数加上疫苗突破病例继续使病毒继续传播 传播到整个社区并导致高发病率和死亡率。目前乙肝治疗的局限性 病毒复制，但不能治愈乙型肝炎病毒感染。因此，迫切需要创新 治疗乙型肝炎病毒感染并为感染者提供持久治愈的疗法。 宿主定向疗法（HDT）在这方面提供了一种有前途的方法。与其针对病毒本身， HDT 以宿主为目标，限制必需的生长因子或上调先天防御。通过瞄准 宿主攻击病毒，传统的抗病毒耐药机制被规避。我们正在开发一个 靶向宿主模式识别视黄酸诱导基因-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，这是一种方法 经临床前研究验证，可保护小鼠免受多种 RNA 和 DNA 病毒的侵害。我们的初步数据显示 RIG-I 激动剂 RAR 不仅可以阻止 HBV 复制，甚至还可以清除细胞中的 HBV DNA 任何已批准的乙肝治疗方法都无法实现这一目标。在本文提出的研究中，我们将进行关键的 配方优化以创建最终产品以测试其抗乙型肝炎病毒感染的功效。我们会优化 两种临床相关纳米颗粒制剂的参数，包括我们的新型纳米颗粒乳液， 有效保护和传递体内RNA。我们将优化配方参数并向下选择最终的 通过测量先天性后体内肝脏、血液和脾脏的细胞因子释放模式来配制制剂 免疫激动剂递送。将测试先导配方 RAR 复合物的抗 HBV 感染功效 体外。 到目前为止，在开发先天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）的专业知识将允许 我们使用各种纳米颗粒配方来安全有效地递送这种 RNA RIG-I 激动剂 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宿主- 作为我们 II 期研究的一部分，将 RNA 分子引入临床前开发和体内功效研究。