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： 尽管有安全有效的疫苗，但B型肝炎病毒（HBV）仍然是一个主要问题， 慢性感染全球约3亿人，每年造成50多万人死亡。高 大量未接种疫苗的人加上疫苗突破性病例，继续使病毒 在整个社区传播，并造成高发病率和高死亡率。目前的HBV治疗限制 病毒复制，但不能治愈HBV感染。因此，迫切需要创新 治疗HBV感染并为受感染个体提供持久治愈的治疗剂。 宿主导向疗法（HDTs）在这方面提供了一种有前途的方法。而不是针对病毒本身， HDTs靶向宿主以限制必需的生长因子或上调先天防御。通过靶向 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 一种靶向宿主模式识别的维甲酸诱导基因-I（RIG-I）的广谱抗病毒RNA分子 一种识别病毒RNA以触发先天性抗病毒免疫反应的方法， 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，甚至可以清除细胞中的HBV DNA， 任何已批准的HBV治疗都无法实现。在本文提出的研究中，我们将对 制剂优化以产生待测试针对HBV感染的功效的最终产品。我们将优化 两种临床相关的纳米颗粒制剂的参数，包括我们的新型纳米颗粒乳剂， 在体内有效地保护和递送RNA。我们将优化配方参数并向下选择最终的 通过测量先天免疫后肝、血和脾的体内细胞因子释放模式， 免疫激动剂递送。将测试先导制剂RAR复合物对HBV感染的疗效 体外 在这一点上，在开发先天免疫激动剂作为治疗剂方面临床上几乎没有取得进展。我们 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制剂来安全有效地将这种RNA RIG-I激动剂递送给 慢性感染者。根据第一阶段项目的结果，我们将推进我们的配方主机- 指导RNA分子进入临床前开发和体内功效研究，作为我们II期研究的一部分。