RP2: Broad Spectrum SiRNA Marburg

RP2：广谱 siRNA 马尔堡

• 批准号: 9017914
• 负责人: IAN MACLACHLAN
• 金额: $ 25.1万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9017914
• 关键词: Angola; Base Pairing; Base Sequence; Caring; Categories; Cavia; Cells; Code; Collaborations; Combined Modality Therapy; Democratic Republic of the Congo; Diagnosis; Disease; Ebola virus; Encapsulated; Ensure; Filovirus; Formulation; Frankfurt-Marburg Syndrome Virus; Funding; Genomic Segment; Goals; Guanosine; Human; In Vitro; Individual; Infection; Life; Lipids; Literature; Macaca; Macaca mulatta; Medical; Messenger RNA; Monoclonal Antibodies; National Institute of Allergy and Infectious Disease; Nucleic Acids; Nucleic acid sequencing; Nucleosides; Pharmaceutical Preparations; Phase; Polymerase; Populations at Risk; RNA Sequences; Recombinants; Research Proposals; Series; Site; Small Interfering RNA; Stomatitis; Sudan; Technology; Testing; Therapeutic; Uridine; Vaccines; Vesicular stomatitis Indiana virus; Viral Hemorrhagic Fevers; Virus; Virus Diseases; anti-viral efficacy; base; clinically relevant; combinatorial; design; efficacy testing; improved; in vitro activity; interest; nanoparticle; nonhuman primate; pathogen; programs; research study; therapeutic target; treatment strategy

The filoviruses, Ebola virus (EBOV) and Marburg virus (MARV), are HHS Tier 1 Category A priority pathogens that cause severe and often fatal hemorrhagic fever (HF) in humans. There are presently no approved therapeutics for EBOV or MARV infections, and a broad spectrum post-exposure treatment conferring protection across all medically relevant EBOV species and MARV strains does not exist. Tekmira currently is developing therapeutics targeting Zaire ebolavirus (ZEBOV) and MARV formulated as Lipid Nanoparticles (LNP). Tekmira's LNP platform stabilizes encapsulated siRNA and ensures effective delivery to disease sites and target cells. The goal of this research proposal is to generate a single broad spectrum siRNA-LNP targeting the most clinically relevant MARV strains and EBOV species (ZEBOV, Sudan ebolavirus (SEBOV) and Bundibugyo ebolavirus (BEBOV)). This therapeutic will then be used in a combinatorial treatment strategy with either recombinant vesicular stomatitis virus (rVSV)-based post exposure vaccines from RPI or fully human anti-filovirus monoclonal antibodies from RP2 described elsewhere in this CETR application. This combinatorial strategy is intended to provide an effective and complementary treatment of filovirus infection that is more effective than each therapeutic alone. To overcome EBOV and MARV sequence divergence and develop a broad spectrum siRNA therapeutic, two strategies will be pursued. The first strategy (Aim 1) will identify siRNA candidates having the most activity against one or more of the EBOV and MARV species. Individual siRNAs will then be combined in a "cocktail" within a single LNP formulation to enable broad spectrum targeting. The second strategy (Aim 2) will allow us to reduce the number of different siRNA within the cocktail through the use of universal "neutral" bases which are able to pair with multiple nucleosides. Incorporation of one or more neutral bases in our siRNA sequence will allow targeting regions of incomplete sequence conservation among filovirus species. The most effective broad spectrum candidate siRNAs will then be encapsulated within a single LNP and tested for activity in nonhuman primates (Aim 3). Following these studies, a single broad spectrum siRNA-LNP therapeutic will be selected for assessment in combinatorial post exposure treatment studies in close collaboration with RPI and RP2 (Aim 4).

丝状病毒、埃博拉病毒 (EBOV) 和马尔堡病毒 (MARV) 是 HHS Tier 1 A 类优先病原体，可导致人类严重且往往致命的出血热 (HF)。目前还没有批准的针对 EBOV 或 MARV 感染的治疗方法，并且不存在为所有医学相关的 EBOV 物种和 MARV 毒株提供保护的广谱暴露后治疗。 Tekmira 目前正在开发针对扎伊尔埃博拉病毒 (ZEBOV) 和配制为脂质纳米颗粒 (LNP) 的 MARV 的疗法。 Tekmira 的 LNP 平台可稳定封装的 siRNA，并确保有效递送至疾病部位和靶细胞。本研究提案的目标是生成针对临床上最相关的 MARV 毒株和埃博拉病毒物种（ZEBOV、苏丹埃博拉病毒 (SEBOV) 和本迪布焦埃博拉病毒 (BEBOV)）的单一广谱 siRNA-LNP。然后，该治疗剂将用于与来自 RPI 的基于重组水泡性口炎病毒 (rVSV) 的暴露后疫苗或来自 RP2 的全人抗丝状病毒单克隆抗体的组合治疗策略，如本 CETR 申请中其他地方所述。这种组合策略旨在提供一种有效且互补的丝状病毒感染治疗方法，比单独使用每种治疗方法更有效。为了克服 EBOV 和 MARV 序列差异并开发广谱 siRNA 治疗药物，将采取两种策略。第一个策略（目标 1）将鉴定对一种或多种 EBOV 和 MARV 物种具有最强活性的 siRNA 候选物。然后，各个 siRNA 将在单一 LNP 制剂中组合成“鸡尾酒”，以实现广谱靶向。第二种策略（目标 2）将允许我们通过使用能够与多个核苷配对的通用“中性”碱基来减少混合物中不同 siRNA 的数量。在我们的 siRNA 序列中掺入一个或多个中性碱基将允许靶向丝状病毒物种之间不完全序列保守的区域。然后，最有效的广谱候选 siRNA 将被封装在单个 LNP 中，并在非人类灵长类动物中测试活性（目标 3）。在这些研究之后，将选择单一广谱 siRNA-LNP 治疗剂，与 RPI 和 RP2 密切合作，在组合暴露后治疗研究中进行评估（目标 4）。