Transient Gene Therapy as Broad Spectrum Antiviral

项目摘要 目前抗病毒药物很少，没有广谱抗病毒药物。例如，甲型流感 仅在美国，IAV病毒（IAV）每年就导致12，000 - 56，000人死亡和150，000 - 750，000人住院治疗，尽管 疫苗和五种FDA批准的药物的可用性1，2.对五种现有药物中的两种产生耐药性， 已经出现13.第二，SARS-CoV-2是一种导致COVID-19的病毒，导致了前所未有的死亡人数 国际吧目前还没有针对其他冠状病毒的抗SARS-Cov-2药物。 I型干扰素（IFN）是提供针对病毒感染的保护的宿主细胞因子。有几 IFN负调控的不同层，ISG 15/USP 18宿主蛋白4、5、6、7复合物负责 抑制IFN炎症的尾端。已经鉴定了人ISG 15敲除，并显示其控制 IAV和SARS-CoV-2复制优于WT对应物。 基于这些ISG 15缺陷个体提供的有效性和安全性证据，Lab 11 Therapeutics 正在开发新的药物，旨在增强IAV控制的瞬时宿主模拟修饰mRNA疗法 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，Lab 11 Therapeutics必须证明其安全性， 在进行人体体内研究之前，在动物模型中进行有效性研究。 该STTR旨在在IAV和SARS-CoV 2感染的动物模型中测试我们的modRNA鸡尾酒药物。的 第一阶段的假设是，modRNA鸡尾酒鼻内递送将限制IAV在小鼠和SARS中的复制- 仓鼠中的CoV-2感染。我们将在特定目标1中通过评估modRNA的作用来检验这一假设。 在人和鼠细胞系中对IAV的作用，随后在小鼠中进行体内测试。在具体目标2中，我们将评估 modRNA在人类和仓鼠细胞系中对SARS-CoV-2的影响，随后在仓鼠中进行体内测试。 在第二阶段，我们建议测试不同的递送模式和modRNA的修饰，以优化最佳的递送模式。 有效递送和抗病毒保护。 全球流感市场价值约50亿美元，其中约五分之一与非疫苗有关 产品. Lab 11 Therapeutics的目标患者人群将是数亿人， 普通民众。考虑到IFN在控制许多病毒感染（ISG 15缺陷细胞）中的关键作用， 已经显示对照比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-CoV 2的先导药物可能也对其他病毒性疾病有效。 这将为Lab 11 Therapeutics提供许可不同产品的机会， 在逐个适应症的基础上建立行动机制。

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.