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

基本信息

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
项目类别：
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

项目摘要

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.

概括目前的结核病多药消除疗法可消除大多数结核分枝杆菌（Mtb）中的前2-3种细菌这段时间后的剩余人口（1%）已成为结核病的“噩梦”。为了消灭这 1% 的耐药细菌，目前的多药治疗必须继续下去。在治疗的最初几周内，患者的健康状况迅速改善，其中许多人退出了治疗。后者促进了耐多药结核菌菌株的出现和扩大。（MDR）和由这些菌株引起的新结核病病例更加难以治愈。建议使用免疫治疗方法更快地根除耐药杆菌。相信可以通过免疫衍生增强宿主（患者）消灭杆菌的能力我们的初步研究表明，裸露的小干扰RNA的递送。 [siRNA] 转录物靶向 TGF¿ 1 细胞因子长期降低小鼠肺部细菌负荷此外，在没有 IL-10 细胞因子的情况下，这种作用会增强。探索我们是否可以通过金纳米粒子传递 siRNA 来改进这种治疗方法。新型多价 siRNA 金纳米粒子缀合物 (siRNA-GNP) 将用于沉默 tgf 的表达¿ 1 或 il10 转录物在慢性感染 Mtb 的小鼠的肺部。 TGF 的 mRNA 沉默¿ 1和IL-10可以增强耐药杆菌的清除我们的长期目标。的目标是缩短结核病治疗时间并治疗慢性耐多药结核病感染，结果将通过以下方式记录。全面的细菌学、免疫学、病理学方法现在是我们实验室的常规方法。独特地配备了最先进的 BSL-III 研究设施，并组建了一支高素质的团队经验丰富的研究人员，在分枝杆菌感染和真核生物 RNA 调控领域拥有专业知识细胞。