siRNA-nanoparticles host targeted immunotherapy for tuberculosis

siRNA 纳米颗粒作为结核病靶向免疫疗法的宿主

• 批准号: 8638299
• 负责人: Mercedes Gonzalez-Juarrero
• 金额: $ 23.78万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8638299
• 关键词: Adjuvant; Animal Model; Antitubercular Agents; Award; Bacillus (bacterium); Bacteria; Cells; Chronic; Containment; Country; Data; Development; Diagnostic; Drug Targeting; Environment; Equilibrium; Eukaryotic Cell; Extreme drug resistant tuberculosis; Funding; Gene Silencing; Goals; Gold; Immune; Immune Targeting; Immune response; Immunologics; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; In Vitro; Incidence; Infection; Interleukin-10; Intervention; Laboratories; Lung; Messenger RNA; Multi-Drug Resistance; Multidrug-Resistant Tuberculosis; Mus; Mycobacterium Infections; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Personal Satisfaction; Phagocytes; Pharmaceutical Preparations; Pharmacotherapy; Population; Production; Protocols documentation; RNA; Regimen; Regulation; Research Personnel; Residual state; Small Interfering RNA; Staging; System; Techniques; Testing; Therapeutic; Time; Transcript; Tuberculosis; Vaccines; Wild Type Mouse; bactericide; chemotherapy; cytokine; design; drug clearance; experience; improved; in vivo; macrophage; nanoparticle; nanotherapeutic; non-compliance; novel; novel therapeutics; public health relevance; research facility; resistant strain; therapeutic target; tuberculosis treatment

Summary The current TB multidrug therapy eliminates the majority of the M. tuberculosis (Mtb) bacteria in the first 2-3 weeks of treatment. The residual population (1%) after this period of time has become a "night mare" for TB eradication. To eliminate this 1% of drug tolerant bacteria the current multidrug treatment has to be continued for 9 month. Patient's well-being improves rapidly in the first weeks of treatment and many of them withdraw from the therapy. The latter has facilitated the emergence and expansion of multidrug-resistant strains of Mtb (MDR) and new TB cases caused by these strains are even more difficult to cure. The primary goal of this proposal is to more rapidly eradicate drug tolerant bacilli using immunotherapeutic approaches. We believe it is possible to enhance the capacity of the host (patient) to eliminate the bacilli via immune derived bactericidal mechanisms. Our preliminary studies indicate that delivery of naked small interfering RNA [siRNA] transcripts targeting the TGF¿1 cytokine reduces the pulmonary bacterial load of mice chronically infected with Mtb. Moreover, this effect is enhanced in the absence of the IL-10 cytokine. Here we want to explore if we can improve this therapeutic approach by delivering the siRNA via gold nanoparticles. Thus, novel polyvalent siRNA gold nanoparticle conjugates (siRNA-GNPs) will be used to silence expression of tgf¿1 or il10 transcripts in the lungs of mice with a chronic infection of Mtb. Thereafter we will test if silencing of mRNA for TGF¿1 and IL-10 can enhance clearance of drug tolerant bacilli. Our long term goal is to shorten therapy for TB and to treat chronic MDR-TB infections. The outcomes will be documented using comprehensive bacteriologic, immunologic, pathologic approaches now routine in our laboratory. We are uniquely equipped with state-of-the-art BSL-III research facilities and have assembled a team of highly experienced researchers with expertise in the fields of mycobacteria infection and RNA regulation in eukaryotic cells.

总结 目前的结核病多药治疗消除了大部分的M。结核病（Mtb）细菌在前2-3 数周的治疗。这段时间后的剩余人口（1%）已成为结核病的“夜魔” 根除为了消除这1%的耐药细菌，必须继续目前的多药治疗 9个月。患者的健康状况在治疗的头几周迅速改善，其中许多人退出治疗。 从治疗中恢复过来后者促进了耐多药结核分枝杆菌菌株的出现和扩大 (MDR)由这些菌株引起的新结核病病例更难治愈。这个的主要目标 建议使用免疫方法更快速地根除耐药杆菌。我们 我相信有可能通过免疫源性增强宿主（患者）消除杆菌的能力， 杀菌机制我们的初步研究表明，递送裸小干扰RNA 靶向TGF β 1细胞因子的[siRNA]转录物长期降低小鼠肺部细菌负荷 感染了Mtb。此外，这种作用在不存在IL-10细胞因子的情况下增强。这里我们要 探索我们是否可以通过金纳米颗粒递送siRNA来改进这种治疗方法。因此，在本发明中， 一种新型的多价siRNA金纳米颗粒结合物（siRNA-GNP）将被用于沉默TGF β 1的表达， 或IL-10转录物在慢性感染Mtb的小鼠肺中的表达。然后我们将测试， TGF β 1和IL-10的mRNA沉默可增强耐药杆菌的清除。我们的长期目标 是缩短结核病的治疗和治疗慢性耐多药结核病感染。结果将使用 全面的细菌学、免疫学、病理学方法现在在我们实验室是常规的。我们 独特地配备了最先进的BSL-III研究设施，并组建了一支高度专业化的团队。 在分枝杆菌感染和真核生物RNA调控领域具有专业知识的经验丰富的研究人员 细胞