Statins as Adjunctive, Host-Directed Therapy for TB

他汀类药物作为结核病的辅助、宿主导向疗法

• 批准号: 9522566
• 负责人: Petros C Karakousis
• 金额: $ 140.45万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-25 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9522566
• 关键词: Adult; Alpha Cell; Animal Model; Antimicrobial Effect; Antimycobacterial Agents; Antitubercular Agents; Autophagocytosis; Award; C3HeB/FeJ Mouse; Cell Culture Techniques; Cells; Centers for Disease Control and Prevention (U.S.); Characteristics; Cholesterol; Chronic; Chronic lung disease; Clinical; Clinical Microbiology; Clinical Research; Clinical Trials; Clinical/Radiologic; Collaborations; Companions; Data; Disease; Dose; Drug Interactions; Epidemiology; Evaluation; Exposure to; Fatty acid glycerol esters; Future; Germ; Granuloma; Growth; HIV; Health Benefit; Histologic; Histology; Human; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immune; Immune response; Immune system; In Vitro; Infection; Inflammatory; Knowledge; Laboratories; Lead; Lipids; Lung; Lung Inflammation; Measures; Mediating; Microbiology; Modeling; Mus; Mycobacterium tuberculosis; Necrosis; New Jersey; Outcome; PET/CT scan; Participant; Pathway interactions; Patients; Persons; Phagosomes; Pharmaceutical Preparations; Pharmacology; Phase; Phase II Clinical Trials; Phenotype; Plasma; Production; Property; Publishing; Pulmonary Pathology; Pulmonary Tuberculosis; Randomized; Recruitment Activity; Regimen; Research Personnel; Respiratory physiology; Role; Safety; Simvastatin; South Africa; South African; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Sputum; Testing; Time; Toxic effect; Tuberculosis; United States National Institutes of Health; Universities; bactericide; base; chemokine; clinical research site; clinically relevant; co-infection; curative treatments; cytokine; design; efficacy study; host organism interaction; immunoregulation; improved; in vitro Assay; in vivo; inhibitor/antagonist; interest; killings; lipid metabolism; macrophage; medical schools; mevalonate; mouse model; multidisciplinary; novel; pathogen; phase 3 study; phase III trial; preclinical study; public health relevance; pulmonary granuloma; research clinical testing; response; treatment duration; tuberculosis drugs; tuberculosis treatment

 DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (Mtb) is known to subvert immune responses to establish infection and cause disease. Thus, host-directed therapy (HDT), as adjunctive treatment to traditional antitubercular regimens, is an attractive strategy. In this proposal, we will investigate the novel hypothesis that statins (HMG-CoA reductase inhibitors) can serve as adjunctive HDT, permitting treatment shortening for drug-susceptible TB and improving lung inflammation and function. Among the most commonly prescribed drugs, statins have lipid-lowering and immunomodulatory properties. Accumulation of lipids in macrophages harboring Mtb has been associated with persistence and phenotypic tolerance to front-line drugs, which leads, in turn, to prolonged treatment duration. We and others have shown that statins, while lacking a direct antimicrobial effect, reduce Mtb growth and infection-induced lipid accumulation in macrophages, and promote phagosomal maturation and autophagy. We also have demonstrated that adjunctive therapy with simvastatin enhances the bactericidal activity of the first-line anti-TB regimen in a standard mouse model of chronic TB infection and reduces the time required for cure. Furthermore, statins have been shown to reduce TB-induced lung pathology in the mouse model. In this application, we propose preclinical studies in macrophages and in a clinically relevant murine model that will allow us to compare activity and exposure-response relationships of various statins and to identify the most promising compound and doses to test clinically. Upon selection of the "lead" statin, we will conduct a two-stage, proof-of-concept clinical trial, in which patients with drug-susceptible, pulmonary TB (with or without HIV co-infection) will be recruited through existing NIH- and South African MRC-supported clinical sites in Soweto and Matlosana, South Africa. Participants in Stage 1 will be randomized to receive the first-line antitubercular regimen with or without the lead statin provided at two different doses for evaluation of safety, PK, and drug interactions, and for selecting the statin dose for Stage 2. In Stage 2, we will determine the ability of the statin, when given in combination with first-line TB treatment, to shorten the time required for sputum culture conversion to negative, as well as other secondary clinical, radiological, microbiological, and laboratory-based outcomes. The plasma concentrations of statin measured in the clinical trial, as well as published data, will be used to guide statin exposures to elucidae the statin's effects on known anti-TB mechanisms of macrophages, including infection-induced lipid accumulation, phagosome maturation and autophagy, and secretion of pro-inflammatory cytokines. This knowledge will help design future Phase III studies. Our proposal leverages an ongoing collaboration between multidisciplinary teams of investigators at Johns Hopkins University School of Medicine, University of the Witwatersrand DST/NRF Centre of Excellence, and Rutgers New Jersey Medical School. Our findings have the potential to substantially advance our understanding of host-organism interactions and clinically validate statins as an adjunctive HDT that can shorten the duration of TB treatment and improve lung function-related outcomes.

 描述（由申请人提供）：已知结核分枝杆菌（Mtb）会破坏免疫反应以建立感染并引起疾病，因此，宿主定向治疗（HDT）作为传统抗结核治疗方案的辅助治疗是一种有吸引力的策略。根据提议，我们将提出新的假设，即他汀类药物（HMG-CoA 还原酶抑制剂）可以作为辅助 HDT，从而缩短治疗时间在最常用的处方药物中，他汀类药物具有降脂和免疫调节的特性，而携带结核分枝杆菌的巨噬细胞中的脂质积累与一线药物的持久性和表型耐受性有关。我们和其他人已经证明，他汀类药物虽然缺乏直接的抗菌作用，但可以减少结核分枝杆菌的生长和感染引起的巨噬细胞中的脂质积累，并促进巨噬细胞的脂质积累。我们还证明，辛伐他汀的辅助治疗可增强慢性结核病标准小鼠模型中一线抗结核治疗方案的杀菌活性。 此外，他汀类药物已被证明可以减少小鼠模型中结核病引起的肺部病理，我们建议在巨噬细胞和临床相关的小鼠模型中进行临床前研究，以便我们进行比较。各种他汀类药物的活性和暴露-反应关系，并确定最有希望进行临床测试的化合物和剂量。在选择“主导”他汀类药物后，我们将进行两阶段的概念验证临床试验，其中，药物敏感肺结核患者（合并或不合并 HIV 感染）将通过 NIH 和南非 MRC 支持的位于南非索韦托和马特洛萨纳的现有临床中心招募，第一阶段的参与者将被随机分组​​。接受一线抗结核治疗方案，含或不含两种不同剂量的先导他汀类药物，以评估安全性、PK 和药物相互作用，并选择第 2 阶段的他汀类药物剂量。在第 2 阶段，我们将确定他汀类药物与一线结核病治疗联合使用时缩短痰培养转阴性所需时间的能力，以及其他次要临床、放射学、微生物学和实验室结果的血浆浓度。临床试验中测量的他汀类药物的含量以及已发表的数据将用于指导他汀类药物暴露于阐明他汀类药物对已知的巨噬细胞抗结核机制的影响，包括感染诱导的脂质积累，这些知识将有助于设计未来的 III 期研究，该研究利用了约翰·霍普金斯大学医学院、威特沃特斯兰德大学 DST/NRF 中心的多学科研究团队之间的持续合作。卓越奖和罗格斯新泽西医学院的研究结果有可能极大地促进我们对宿主-生物体相互作用的理解，并且经临床验证的他汀类药物作为辅助 HDT 可以缩短治疗的持续时间。结核病治疗并改善肺功能相关结果。