Transient Gene Therapy as Broad Spectrum Antiviral

项目摘要 目前抗病毒药物很少，也没有广谱抗病毒药物。例如，甲型流感 仅在美国，病毒(IAV)每年就导致12,000-56,000人死亡和150,000-750,000人住院，尽管 疫苗和FDA批准的五种药物的可获得性1，2。对现有五种药物中的两种产生抗药性 已经出现了13.第二，引起COVID19的SARS-CoV-2病毒导致前所未有的死亡人数 全世界。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)是一种宿主细胞因子，提供对病毒感染的保护。有几个 不同层次的干扰素负调控，而ISG15/USP18宿主蛋白复合体4、5、6、7负责 抑制干扰素的末梢炎症。人类ISG15基因敲除已被识别并显示为控制 IAV和SARS-CoV-2的复制效果优于西药。 基于这些ISG15缺陷个体提供的有效性和安全性证据，Lab11 Treateutics 正在开发旨在加强IAV控制的新药，即瞬时模仿宿主的修改的mRNA疗法 和SARS-CoV-2在普通人群中的感染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测试，但要获得FDA的批准，Lab11治疗公司必须证明安全和 在继续进行人体活体研究之前，在动物模型中的有效性。 这项研究的目的是在IAV和SARS-CoV2感染的动物模型上测试我们的modRNA鸡尾酒药物。这个 第一阶段假设是，经鼻注射的modRNA鸡尾酒将限制IAV在小鼠和SARS中的复制。 仓鼠的冠状病毒2型感染。我们将通过评估modRNAs的影响，在特定目标1中测试这一假设 人和小鼠细胞株中的IAV，然后在小鼠体内进行试验。在具体目标2中，我们将评估 ModRNAs在人和仓鼠细胞系中对SARS-CoV-2的影响，随后在仓鼠体内进行测试。 在第二阶段，我们建议测试不同的modRNAs传递模式和封装，以优化 有效的交付和抗病毒保护。 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。Lab11 Treateutics的目标患者群体将是数亿人 普通民众。鉴于干扰素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疾病有效。 这将为Lab11 Treeutics提供许可使用相同的不同产品的机会 在逐个指征的基础上的行动机制。

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.