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

开发用于预防和治疗病毒感染的 IFN-lambda3

• 批准号: 8784187
• 负责人: Joan E. Durbin
• 金额: $ 118.59万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-18 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8784187
• 关键词: Accidents; Acute; Adverse effects; Animal Model; Antibiotics; Antiviral Agents; Avian Influenza A Virus; Bacterial Infections; Benign; Biological; Biology; Bioterrorism; Cells; Clinic; Communities; Complex; Coronavirus; Development; Diagnostic Procedure; Disease; Disease Outbreaks; Disease Progression; Drug resistance; Engineering; Equus caballus; Event; Family; Fright; Genes; Goals; Health; Host Defense; Human; Immune; Immune system; Immunity; In Vitro; Individual; Infection; Intellectual Property; Interferon Type I; Interferons; Knowledge; Laboratories; Life; Life Cycle Stages; Lymphocyte; Measures; Mediator of activation protein; Medical; Military Personnel; Monkeypox virus; Mus; Mutation; Nature; Opportunistic Infections; Organ; Pathogenesis; Patients; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Population; Positioning Attribute; Prevention; Procedures; Process; Production; Property; Prophylactic treatment; Proteins; Public Health; Race; Research; Research Personnel; Safety; Science; Severity of illness; Signal Pathway; Signal Transduction; Stimulus; Syndrome; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Toxic effect; Vaccination; Viral; Virulence; Virus; Virus Diseases; Virus Replication; Work; authority; base; biodefense; biosafety level 3 facility; cytokine; efficacy testing; improved; in vivo; influenzavirus; interest; member; novel; novel virus; pathogen; preclinical efficacy; prevent; receptor; receptor expression; respiratory; response; scale up; viral detection; virus identification

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-α/ß) and recently identified type III IFNs (IFN-λs), that can independently activate rapid innate antiviral protection in various organs. Importantly, recent studies have started to reveal unique biological features of IFN-λs 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-λ- based therapeutics for biodefense. In aim 1, we will develop procedures to optimize and scale up production of IFN-λ3 and its derivatives for the extensive in vitro and in vivo testing needed to establish its preclinical efficacy. This will include pegylation of IFN-λ3 t improve the stability, deliverability and increase safety of IFN-λ3. In other aims, we will test antiviral properties and mechanisms of action of IFN-λ3-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-λ-based broad-spectrum antiviral therapeutics and bring them into the clinic.

描述（由申请人提供）：人们越来越担心，人类体内自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外获得零星突变或在实验室环境中进行基因改造以实现生物恐怖主义后，可能会进化为有效地感染并在人类中传播。即使诊断技术的发展取得了巨大进步，也可能需要几周的时间才能识别出一种新出现的病毒；开发有效的病毒特异性疗法可能需要几个月（或几年）的时间。因此，在受到性质不明的生物武器攻击平民或军事人员的威胁时，或在攻击后立即，只能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。该机制完全依赖于 干扰素（IFN）。这些小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，并迫使这些细胞采取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。干扰素有两种类型，即 I 型干扰素 (IFN-α/ß) 和最近发现的 III 型干扰素 (IFN-λ)，它们可以独立激活各个器官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-λ 的独特生物学特性，这可能使其成为比 I 型 IFN 更好的抗病毒治疗药物。我们在一家制药公司的参与下组建了一支强大的研究团队，该团队拥有必要的专业知识、知识产权和开发和测试基于 IFN-λ 的生物防御疗法的能力。在目标 1 中，我们将开发优化和扩大 IFN-λ3 及其衍生物生产的程序，以进行广泛的体外和体内测试，以确定其临床前功效。这将包括 IFN-λ3 的聚乙二醇化，以提高 IFN-λ3 的稳定性、递送能力并提高安全性。在其他目标中，我们将在动物感染模型中测试基于 IFN-λ3 的抗病毒药物对各种病毒的抗病毒特性和作用机制，首先在生物安全 2 级 (BSL2) 下，然后在 BSL3 设施中。该项目的长期目标是开发基于IFN-λ的广谱抗病毒疗法并将其引入临床。