Development of IFN-lambda3 for the Prevention and Treatment of Virus Infection

描述（由申请人提供）：人们越来越担心，在人类群体中天然存在的良性病毒或通常存在于非人类宿主中的病毒在野生环境中获得零星突变或在实验室环境中进行生物恐怖主义基因修饰后，可能会进化为有效感染并在人群中传播。即使在诊断技术的发展方面取得了巨大的进步，在可以鉴定新出现的病毒之前可能要经过几个星期;并且可能需要几个月（或几年）来开发有效的病毒特异性疗法。因此，在平民或军事人员受到性质不明的生物武器攻击的威胁下，或在攻击后立即，只有广谱抗病毒药物才能用作预防性治疗，以预防和/或治疗不明病毒剂的感染。数百种不同的病毒能够感染人类;疾病的严重程度可能从无症状的机会性感染到危及生命的病毒性疾病。尽管不同病毒的生物学、生命周期和发病机制大相径庭，但免疫系统主要采用相同的抗病毒保护机制来对抗任何类型的病毒。这种机制完全依赖于 干扰素（IFN）。这些小的分泌蛋白由病毒感染的细胞释放，以警告邻近细胞病毒的存在，并迫使这些细胞部署各种抗病毒保护手段。因此，我们认为应对病毒感染的最佳治疗策略是增强免疫系统的保护性抗病毒力量，而不是针对单个病毒进行治疗干预。有两种类型的干扰素，I型干扰素（IFN-γ/γ）和最近确定的III型干扰素（IFN-γ？s），其可以独立地激活各种器官中的快速先天抗病毒保护。重要的是，最近的研究已经开始揭示IFN-？这可能使它们比I型干扰素更好的抗病毒治疗。我们已经组建了一个强大的研究团队，其中有一家制药公司的参与，该团队拥有必要的专业知识，知识产权和开发和测试IFN-？生物防御的基础疗法。在目标1，我们将制定程序，以优化和规模生产的IFN-？3及其衍生物用于建立其临床前功效所需的广泛的体外和体内测试。这将包括IFN-？3.提高IFN-？3.在其他目标，我们将测试抗病毒特性和IFN-？3-在动物感染模型中使用抗各种病毒的基础抗病毒药物，首先在生物安全级别2（BSL 2），然后在BSL 3设施中使用。本项目的长期目标是开发IFN-？-基于广谱抗病毒疗法并将其引入临床。

DESCRIPTION (provided by applicant): There is a growing concern that naturally existing benign viruses within human population or viruses normally residing in non-human hosts may evolve to efficiently infect and spread through the human population after acquiring sporadic mutations in the wild or being genetically modified in laboratory settings for bioterrorism. Even with enormous advances in the development of diagnostic techniques, several weeks may pass before a novel emerging virus can be identified; and it may take several months (or years) to develop effective virus- specific therapy. Therefore, under the threat of an attack to civilian or military personnel with bioweapons of unknown nature, or immediately after an attack, only broad-spectrum antivirals can be used as a prophylactic treatment to prevent and/or treat infection with an unidentified viral agent. Hundreds of different viruses are able to infect humans; and the severity of the disease may range from asymptomatic opportunistic infections to life-threatening viral diseases. Although the biology, life cycle and pathogenesis of different viruses are widely divergent, the immune system employs mainly the same mechanism of antiviral protection to battle any type of viruses. This mechanism relies entirely on the action of interferons (IFNs). These small secreted proteins are released by virus-infected cells to warn neighboring cells about viral presence and to force these cells to deploy various means of antiviral protection. Thus, we believe that the best therapeutic strategy to deal with viral infections is to enhance protective antiviral forces of the immune system, rather than target an individual virus for therapeutic intervention. There are two types of IFNs, type I IFNs (IFN-¿/¿) and recently identified type III IFNs (IFN-?s), that can independently activate rapid innate antiviral protection in various organs. Importantly, recent studies have started to reveal unique biological features of IFN-?s that may make them better antiviral therapeutics than type I IFNs. We have assembled a strong team of investigators with the participation of a pharmaceutical company, the team that has necessary expertise, intellectual property and capability to develop and test IFN-?- based therapeutics for biodefense. In aim 1, we will develop procedures to optimize and scale up production of IFN-?3 and its derivatives for the extensive in vitro and in vivo testing needed to establish its preclinical efficacy. This will include pegylation of IFN-?3 t improve the stability, deliverability and increase safety of IFN- ?3. In other aims, we will test antiviral properties and mechanisms of action of IFN-?3-base antivirals against various viruses in animal models of infection, first at biosafety level 2 (BSL2) and then at BSL3 facilities. The long-term goal of this project is to develop IFN-?-based broad-spectrum antiviral therapeutics and bring them into the clinic.