Autophagy-based HDT for tuberculosis

 描述（由申请人提供）：本项目的目的是将自噬的治疗潜力转化为基于自噬的宿主导向疗法（AB-HDT），用于控制结核病（TB）。具体重点将放在治疗由多重耐药（MDR）结核分枝杆菌（Mtb）菌株引起的感染上。这一目标的原因是，耐多药结核病的治疗选择受到严重限制，药物治疗方案活性较低，时间较长，毒性大，价格昂贵，而且往往无效，因此耐药结核病的需求最大;第二个原因是更容易评估AB-HDT在这一患者群体中的疗效。实验动物模型中的数据表明自噬的双重作用，每一种对TB中的AB-HDT都有吸引力：直接促进细菌杀灭和抑制有害炎症。我们已经组建了一个由基础科学家（Deretic，Timmins，Salgame）和临床科学家（Ellner，Horsburgh，Joloba）组成的团队，以指导，协调和执行UH 2和UH 3阶段，以提供实际结果并测试AB-HDT可用于对抗Mtb的假设，并证明在临床环境中有益和实用。我们建议根据在临床前模型中确定的比较疗效选择候选药物和给药方案，包括健康人类受试者的U2临床研究、药代动力学/药效学（PK/PD）研究、不良事件特征的考虑。在UH 2阶段，我们将使用细胞和小鼠自噬模型来比较、测试和优化一组候选AB-HDT药物对自噬的增强作用。然后，我们将测试顶级AB-HDT药物在结核病小鼠模型中的疗效。在UH 2阶段期间比较的激动剂药物将是在小鼠TB模型中具有疗效证据的那些和在我们的GGC自噬诱导化合物筛选中鉴定的那些：卡马西平、吉非替尼、伊马替尼、博舒替尼（伊马替尼的备份）、溴己新（来自GGC筛选）、舍曲林、阿托伐他汀、二甲双胍和“开放位置”AB-HDT药物。UH 2阶段的关键交付成果将是鉴定候选HDT药物，这些药物在结核病的标准小鼠气溶胶模型中显示出具有临床意义的疗效潜力。小鼠模型的结果将与药物的已知药理学和安全性特性相结合，以确定最有益的AB-HDT方案将进入UH 3期。在UH 3阶段，我们建议在乌干达研究MDR-TB（±HIV合并感染）患者，因为双重感染的负担在撒哈拉以南非洲最大，并确保AB-HDT在HIV感染的TB患者中发挥治疗作用。我们将在乌干达坎帕拉招募耐多药结核病例，选择坎帕拉作为临床研究中心是因为长期合作，包括耐多药结核研究，最先进的、CAP认证的分枝杆菌参考和研究实验室，适合确保高质量的细菌学终点，并获得足够数量的艾滋病毒感染和未感染艾滋病毒的耐多药结核病例。这些研究将确定AB-HDT是否有足够的前景来保证IIB/III期临床试验， 疗效作为终点。

 DESCRIPTION (provided by applicant): The objective of this project is to convert the therapeutic potential of autophagy to an autophagy-based host- directed therapy (AB-HDT) for control of tuberculosis (TB). The specific emphasis will be on treatment of infections caused by multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) strains. The reasons for this target is that treatment options for MDR-TB are severely limited and drug regimens are less active, lengthy, toxic, expensive and often ineffective so the need is greatest in drug resistant TB; a second reason is the greater ease of assessing efficacy of AB-HDT in this patient population. Data in experimental animal models indicate dual effects of autophagy each attractive for an AB-HDT in TB: direct promotion of bacterial killing and inhibition of injurious inflammation. We have formed a team between basic (Deretic, Timmins, Salgame) and clinician scientists (Ellner, Horsburgh, Joloba) to guide, coordinate, and execute the UH2 and UH3 phases to deliver practical results and test the hypothesis that AB-HDT can be used against Mtb and prove beneficial and practical in the clinical setting. We propose to select the candidate drug and dosage schedule based on determination of comparative efficacy in preclinical models including U2 clinical studies with healthy human subjects, pharmacokinetics/pharmacodynamics (PK/PD) studies, consideration of adverse events profile. In the UH2 phase, we will use cellular and murine models of autophagy to compare, test and optimize enhancement of autophagy by a panel of candidate AB-HDT drugs. We will then test the top AB-HDT drugs for efficacy in the mouse model of TB. The agonist drugs to be compared during the UH2 phase will be those with evidence of efficacy in mouse TB models and those identified in our GGC autophagy-inducing compound screen: carbamazepine, gefitinib, imatinib, bosutinib (a back up for imatinib), bromhexine (from GGC screen), sertraline, atorvastin, metformin and an "open position" AB-HDT drug. The key deliverable of the UH2 phase will be identification of candidate HDT drugs showing potential for clinically meaningful efficacy in standard mouse aerosol models of TB. The results of the mouse model will be integrated with known pharmacologic and safety properties of the drugs to identify the most beneficial AB-HDT regimen will be moved to the UH3 phase. In the UH3 phase, we propose to study patients with MDR-TB (±HIV co-infection) in Uganda because the burden of dual infection is greatest in Sub-Saharan Africa and to assure that AB-HDT exerts a therapeutic effect in HIV-infected TB patients. We will recruit MDR-TB cases in Kampala Uganda, selected as a clinical site because of long-standing collaboration including studies of MDR-TB, the state-of-the art, CAP-certified, mycobacterial reference and research laboratory appropriate to assure high quality bacteriologic endpoints, and access to sufficient numbers of HIV-infected and HIV-uninfected MDR-TB cases. These studies will establish whether an AB-HDT is sufficiently promising to warrant a Phase IIB/III clinical trial with clinical efficacy as an endpoint.