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，在人群中自然存在的良性病毒或通常居住在非人类宿主中的病毒，在野外获得零星突变或在实验室环境中进行生物恐怖主义基因改造后，可能会进化到有效地感染和传播人群。即使诊断技术的发展取得了巨大进步，一种新出现的病毒可能要经过数周才能被识别出来；而且可能需要几个月（或几年）才能开发出有效的病毒特异性治疗方法。因此，在平民或军事人员受到性质不明的生物武器袭击的威胁下，或在袭击发生后立即使用广谱抗病毒药物作为预防性治疗，以预防和/或治疗不明病毒制剂的感染。数百种不同的病毒能够感染人类；该病的严重程度从无症状的机会性感染到危及生命的病毒性疾病不等。尽管不同病毒的生物学、生命周期和发病机制存在很大差异，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。这个机制完全依赖于

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.