siRNA Modulation of the Immune Response

描述（由申请人提供）：NIAID和负责美国生物防御研究战略发展的其他机构表示的一个主要目标是广泛的活动，减轻广泛代理的灾难性生物威胁。这种治疗活性很难确定，需要对免疫系统或病原体有新的理解和范式。新的发现是，减少CD 45（一种与免疫细胞相关的蛋白质）的表达，以保护宿主免受各种致命病原体侵害的方式深刻地调节免疫应答能力，这为靶向宿主免疫系统以实现广谱活性目标的新型治疗干预提供了机会。 该方法是基于使用一系列转基因小鼠表达降低水平的CD 45的发现。降低的CD 45表达显示出提供来自三个类别A（B.炭疽、埃博拉病毒和马尔堡病毒）和一种C类（流感）生物防御病原体。由于这四种病原体代表了高度多样的感染性生物体和病理学，因此CD 45的减少也可能提供针对其他病原体的治疗益处。因此，拟议研究的意义不仅在于从生物防御的角度保护病原体的潜力，而且还在于大流行病的控制。 减少CD 45表达以增强针对生物防御病原体的免疫保护代表了CD 45的一种新的且意想不到的特性，也是一种新的免疫治疗方法。由于当仅存在一个功能性基因拷贝时发生的永久性遗传降低的CD 45表达在小鼠或人中不产生可检测的不良作用，因此诱导CD 45功能瞬时降低的治疗剂很可能具有优异的安全性特征，特别是如果仅靶向CD 45。这种选择性靶向的一种方法是利用CD 45特异性基因序列。CD 45特异性siRNA将使用独特的脂质-聚合物混合纳米颗粒平台递送，以实现选择性CD 45减少。这项可行性研究将测试和推进这项技术，首先使用培养的细胞，然后评估小鼠的CD 45减少和免疫功能调节。

DESCRIPTION (provided by applicant): A major goal expressed by NIAID and other agencies charged with development of the U.S. biodefense research strategy is a broad spectrum activity that mitigates catastrophic biothreats across a wide spectrum of agents. Such therapeutic activities have been difficult to identify and require new understanding and paradigms of the immune system or the pathogens. The novel discovery that reduced expression of CD45, a protein associated with immune cells, profoundly modulates the immune response capability in a manner that protects the host against a variety of lethal pathogens provides opportunities for novel therapeutic interventions that target the host immune system to achieve the goal of a broad spectrum activity. The approach is based on findings using a series of mice genetically modified to express reduced levels of CD45. Reduced CD45 expression was shown to provide survival protection from three Category A (B. anthracis, Ebola virus and Marburg virus) and one Category C (influenza) biodefense pathogens. Since these four pathogens represent highly diverse infectious organisms and pathologies, it is likely that the reduction of CD45 will also provide therapeutic benefit against additional pathogens. Thus, the significance of the proposed studies is not only the potential for pathogen protection from a biodefense standpoint but also for pandemic disease control. The reduction of CD45 expression to enhance immune protection against biodefense pathogens represents a new and unexpected property of CD45 and a novel approach for immunotherapy. Since permanent, genetically-reduced CD45 expression, as occurs when only one functional gene copy is present, produces no detectable adverse effects in mouse or human, a therapeutic that induces transient reduction of CD45 function is very likely to have an excellent safety profile, particularly if only CD45 is targeted. One approach to such selective targeting is to utilze CD45-specific genetic sequences. CD45-specific siRNA will be delivered using a unique lipid-polymer hybrid nanoparticle platform to achieve selective CD45 reduction. This feasibility study will test and advance this technology, initially using cultured cells followed by evaluation of CD45 reduction and modulation of immune function in mice.