Transient Gene Therapy as Broad Spectrum Antiviral

瞬时基因疗法作为广谱抗病毒药物

• 批准号: 10324302
• 负责人: Dusan Bogunovic
• 金额: $ 25.59万
• 依托单位: LAB11 THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10324302
• 关键词: 2019-nCoV; Animal Model; Animals; Antiviral Agents; Antiviral resistance; Biological Process; Biotechnology; COVID-19; Cell Line; Cells; Cessation of life; Complex; Coronavirus; Data; Development; Dose; Emergency Situation; FDA approved; Formulation; General Population; Genes; Germ-Line Mutation; Goals; Hamster Cell Line; Hamsters; Hospitalization; Human; Human Cell Line; ISG15 gene; Immune system; In Vitro; Incidence; Individual; Infection; Inflammation; Influenza; Influenza A virus; Inherited; Interferon Type I; Interferons; Knock-out; Knowledge; Laboratories; Lead; Licensing; Maps; Messenger RNA; Morbidity - disease rate; Mus; Mutation; Natural Immunity; Outcome; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Proteins; Readiness; Regulation; Resistance; Role; SARS-CoV-2 infection; Safety; Small Business Technology Transfer Research; Symptoms; System; Tail; Target Populations; Technology; Testing; Therapeutic; Vaccines; Viral; Virus; Virus Diseases; Virus Replication; Vulnerable Populations; Work; anti-influenza; base; commercial application; cytokine; drug candidate; flu; gene therapy; high risk; in vivo; in vivo evaluation; medical schools; mortality; nanoparticle; novel; novel therapeutics; patient population; phase 1 study; phase 2 study; resistant strain; vaccine access

Project Summary Currently there are very few antiviral drugs, and no broad-spectrum antiviral drugs. For example, Influenza A virus (IAV) causes 12,000-56,000 deaths and 150,000-750,000 hospitalizations annually in the US alone, despite the availability of vaccines and five FDA-approved drugs 1, 2. Resistance to two of the five existing drugs has already emerged 13. Second, SARS-CoV-2 a virus which causes COVID19 led to unprecedented death toll worldwide. Currently there are no anti-SARS-Cov-2 drugs that can target other corona viruses. Type I interferons (IFNs) are host cytokines providing protection against viral infections. There are several different layers of IFN negative regulation, and the ISG15/USP 18 host protein 4, 5, 6, 7 complex is responsible for suppressing the tail end of IFN inflammation. Human ISG15 knockouts have been identified and shown to control IAV and SARS-CoV-2 replication better than WT counterparts. Based on the evidence of efficacy and safety provided by these ISG15-deficient individuals, Lab11 Therapeutics is developing new drugs, transient host-mimicking modified mRNA therapies aimed at enhancing control of IAV and SARS-CoV-2 infection in the general population 4, 6, 7. Candidate drugs are recreating antiviral state identified and tested in the human system, but, for FDA approval, Lab11 Therapeutics must demonstrate safety and efficacy in an animal model, before proceeding with human in vivo studies. This STTR aims to test our modRNA cocktail drugs in animal models of IAV and SARS-CoV2 infection. The phase I hypothesis is that modRNA cocktail delivered intranasally will restrict IAV replication in mice and SARS- CoV-2 infection in hamsters. We will test this hypothesis in Specific Aim 1, by evaluating the effects of modRNAs on IAV in human and murine cell lines followed by in vivo testing in mice. In Specific Aim 2, we will evaluate the effects modRNAs have on SARS-CoV-2 in human and hamster cell lines followed by in vivo testing in hamsters. In Phase II, we propose to test different delivery modes and encapsulations of modRNAs to optimize the most effective delivery and antiviral protection. The global influenza market is valued at about 5 billion dollars, about a fifth of which relates to non-vaccine products. The patient population targeted by Lab11 Therapeutics will be hundreds of millions of individuals in the general population. Given the crucial role of IFN in the control of many viral infections (ISG15-deficient cells control have been shown to control the replication of 14 different viruses more effectively than WT cells), the lead drugs developed here for IAV and SARS-CoV2 are likely to be effective against other viral diseases too. This will provide Lab11 Therapeutics with opportunities for the licensing of different products with identical mechanisms of action on an indication-by-indication basis.

项目概要 目前抗病毒药物很少，更没有广谱抗病毒药物。例如，甲型流感 仅在美国，流感病毒 (IAV) 每年就会导致 12,000-56,000 人死亡和 150,000-750,000 人住院治疗，尽管 疫苗和五种经 FDA 批准的药物的可用性 1, 2. 对五种现有药物中的两种已经产生耐药性 13. 其次，引起新冠肺炎 (COVID19) 的病毒 SARS-CoV-2 导致前所未有的死亡人数 全世界。目前还没有可以针对其他冠状病毒的抗 SARS-Cov-2 药物。 I 型干扰素 (IFN) 是宿主细胞因子，可提供针对病毒感染的保护。有几个 IFN 负调节的不同层，ISG15/USP 18 宿主蛋白 4、5、6、7 复合物负责 抑制 IFN 炎症的尾端。人类 ISG15 敲除已被鉴定并被证明可以控制 IAV 和 SARS-CoV-2 复制优于 WT 复制品。 基于这些 ISG15 缺陷个体提供的有效性和安全性证据，Lab11 Therapeutics 正在开发新药、短暂模仿宿主的修饰 mRNA 疗法，旨在增强对 IAV 的控制 和普通人群中的 SARS-CoV-2 感染 4、6、7。候选药物正在重建已确定的抗病毒状态 并在人体系统中进行了测试，但是，为了获得 FDA 的批准，Lab11 Therapeutics 必须证明安全性和 在进行人体体内研究之前，先在动物模型中验证疗效。 该 STTR 旨在在 IAV 和 SARS-CoV2 感染的动物模型中测试我们的 modRNA 鸡尾酒药物。这 第一阶段的假设是，鼻内递送的 modRNA 混合物将限制 IAV 在小鼠和 SARS 中的复制 仓鼠中的 CoV-2 感染。我们将在具体目标 1 中通过评估 modRNA 的效果来检验这一假设 在人类和小鼠细胞系中进行 IAV，然后在小鼠体内进行测试。在具体目标 2 中，我们将评估 modRNA 对人类和仓鼠细胞系中的 SARS-CoV-2 的影响，然后在仓鼠体内进行测试。 在第二阶段，我们建议测试不同的递送模式和 modRNA 的封装，以优化最优化 有效的传递和抗病毒保护。 全球流感市场价值约50亿美元，其中约五分之一与非疫苗相关 产品。 Lab11 Therapeutics 的目标患者群体将是数亿人 普通民众。鉴于 IFN 在控制许多病毒感染（ISG15 缺陷细胞）中的关键作用 对照已被证明比 WT 细胞更有效地控制 14 种不同病毒的复制）， 这里开发的针对 IAV 和 SARS-CoV2 的先导药物也可能对其他病毒性疾病有效。 这将为 Lab11 Therapeutics 提供相同的不同产品的许可机会。 逐个适应症的行动机制。