Sputum Transcriptomic Expression Profiling in Study 31: Express 31

研究 31 中的痰转录组表达谱：Express 31

• 批准号: 10245036
• 负责人: John Lucian Davis
• 金额: $ 88.74万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-03 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10245036
• 关键词: AIDS clinical trial group; Affect; Bacillus; Biological; Centers for Disease Control and Prevention (U.S.); Characteristics; Chest; Clinical; Clinical Trials; Code; Computing Methodologies; DNA Gyrase; DNA Repair; DNA-Directed RNA Polymerase; Data; Development; Dose; Drug Exposure; Drug Kinetics; Drug Targeting; Drug Tolerance; Enrollment; Evaluation; Expression Profiling; Fluoroquinolones; Future; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic Transcription; Genotype; Germ; Goals; HIV; Kenya; Longterm Follow-up; Measurable; Measures; Messenger RNA; Microbiology; Modeling; Molecular; Monitor; Moxifloxacin; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Outcome; Pathway interactions; Patients; Peru; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacotherapy; Phase; Phase III Clinical Trials; Phenotype; Physiological; Physiological Adaptation; Physiology; Plant Roots; Population; Proteins; Protocols documentation; Pulmonary Tuberculosis; RNA; Randomized Clinical Trials; Regimen; Relapse; Research; Resources; Rifamycins; Safety; Site; Sputum; Surrogate Endpoint; Surrogate Markers; System; Testing; Transcript; Treatment outcome; Tuberculosis; Uganda; Vietnam; bactericide; base; case control; cohort; design; diverse data; drug development; drug mechanism; efficacy evaluation; emerging pathogen; functional adaptation; genome-wide; high risk; in vivo; insight; molecular marker; next generation; novel; novel marker; open label; pathogen; pharmacodynamic biomarker; pharmacokinetic model; phase III trial; preservation; programs; public health priorities; radiological imaging; relapse prediction; relapse risk; response; rifapentine; transcriptome; transcriptomics; treatment arm; tuberculosis drugs; tuberculosis treatment

PROJECT SUMMARY/ ABSTRACT Developing shorter, safer, more effective drug regimens for active tuberculosis (TB) is a critical public health priority. However, a lack of reliable intermediate clinical trial endpoints constrains accurate regimen selection for Phase 3 trials. Moreover, current surrogate markers cannot explain the root causes of poor outcomes, namely the functional adaptations that enable survival of genetically-susceptible, drug-tolerant M. tuberculosis (Mtb) subpopulations. Our objective is to evaluate sputum Mtb transcriptional profiling as a novel biomarker for predicting relapse and as a surrogate endpoint for clinical trials. Our central hypothesis is that TB treatment outcomes are driven by Mtb physiologic changes measurable via pathogen-targeted transcriptional profiling. Our long-term objective is to develop novel surrogate markers and provide new biologic insights into drug tolerance through direct, in vivo molecular monitoring of Mtb populations during treatment. Our scientific approach will be to perform sputum Mtb transcriptional profiling in culture-confirmed, drug-susceptible pulmonary TB patients co-enrolled in a large, Phase 3, open-label, randomized clinical trial led by the CDC TB Trials Consortium (TBTC) and the NIAID/DAIDS AIDS Clinical Trials Group (ACTG). Study 31/ACTG 5349 will compare two 4-month, high-dose rifapentine-based regimens (one including a fluoroquinolone) with standard 6-month TB treatment. At sites in Kenya, Peru, Uganda, and Vietnam, we will collect RNA-preserved sputum at baseline and throughout treatment from patients at high risk of relapse, including HIV-infected patients, and HIV-uninfected patients with cavitation on baseline chest radiograph. In Aim 1, we will perform genome-wide Mtb transcriptional profiling in protocol-correct patients in each treatment arm to provide a comprehensive roadmap of physiologic and pharmacodynamic effects of TB treatment on the Mtb transcriptome, with biological interpretations of key drug-tolerance pathways. Specifically, we will test hypotheses that transcriptional changes specific to drug mechanism of action can serve as pharmacodynamic markers, as well as distinct hypotheses related to rifamycin and moxifloxacin exposure levels. In Aim 2, we will perform Mtb transcriptional profiling in all culture-/genotype-confirmed relapses and matched controls with relapse-free cure. We will build advanced pharmacokinetic models to select Mtb transcripts that can accurately predict relapse and serve as surrogate endpoints for clinical trials. Aim 2 will also produce an integrative systems pharmacology model to explain between-patient differences in treatment outcomes. Our research program has the potential to inaugurate a new era in which drug-development is based not on culture-based surrogates but on precise, in vivo molecular markers of pathogen physiologic state during TB treatment.

项目概要/摘要 开发针对活动性结核病 (TB) 的更短、更安全、更有效的药物治疗方案对于公共卫生至关重要 优先事项。然而，缺乏可靠的中间临床试验终点限制了准确的治疗方案选择 用于第三阶段试验。此外，目前的替代标记无法解释不良结果的根本原因， 即使遗传易感、耐药的结核分枝杆菌得以生存的功能适应 (MTB) 亚群。我们的目标是评估痰 Mtb 转录谱作为新型生物标志物 预测复发并作为临床试验的替代终点。我们的中心假设是结核病治疗 结果是由可通过病原体靶向转录谱测量的结核分枝杆菌生理变化驱动的。 我们的长期目标是开发新型替代标记并为药物提供新的生物学见解 通过在治疗期间对结核分枝杆菌种群进行直接体内分子监测来确定耐受性。我们的科学 方法是在培养确认的、药物敏感的样本中进行痰 Mtb 转录谱分析 肺结核患者共同参加了由 CDC TB 牵头的大型 3 期开放标签随机临床试验 试验联盟 (TBTC) 和 NIAID/DAIDS 艾滋病临床试验组 (ACTG)。研究 31/ACTG 5349 将 将两种为期 4 个月的高剂量利福喷丁治疗方案（一种包括氟喹诺酮类药物）与标准治疗方案进行比较 6 个月的结核病治疗。在肯尼亚、秘鲁、乌干达和越南的地点，我们将在以下地址收集保存 RNA 的痰液： 复发高风险患者（包括艾滋病毒感染者）的基线和整个治疗过程，以及 未感染 HIV 的患者在基线胸部 X 光片上出现空洞。在目标 1 中，我们将进行全基因组 对每个治疗组中符合方案的患者进行 Mtb 转录谱分析，以提供全面的结果 结核病治疗对 Mtb 转录组的生理和药效学影响路线图，其中 关键药物耐受途径的生物学解释。具体来说，我们将测试以下假设： 药物作用机制特有的转录变化也可以作为药效学标记 作为与利福霉素和莫西沙星暴露水平相关的不同假设。在目标 2 中，我们将进行 Mtb 所有经培养/基因型确认的复发和无复发的匹配对照中的转录分析 治愈。我们将建立先进的药代动力学模型来选择能够准确预测的 Mtb 转录本 复发并作为临床试验的替代终点。目标 2 还将产生一个综合系统 药理学模型来解释患者之间治疗结果的差异。我们的研究计划有 有可能开创一个新时代，在这个时代中，药物开发不再基于文化替代品，而是基于 结核病治疗期间病原体生理状态的精确体内分子标记。

项目成果

Transcriptional adaptation of Mycobacterium tuberculosis that survives prolonged multi-drug treatment in mice.

• DOI: 10.1128/mbio.02363-23
• 发表时间: 2023-12-19
• 期刊: MBIO
• 影响因子: 6.4
• 作者: Wynn, Elizabeth A.;Dide-Agossou, Christian;Reichlen, Matthew;Rossmassler, Karen;Al Mubarak, Reem;Reid, Justin J.;Tabor, Samuel T.;Born, Sarah E. M.;Ransom, Monica R.;Davidson, Rebecca M.;Walton, Kendra N.;Benoit, Jeanne B.;Hoppers, Amanda;Loy, Dorothy E.;Bauman, Allison A.;Massoudi, Lisa M.;Dolganov, Gregory;Strong, Michael;Nahid, Payam;Voskuil, Martin I.;Robertson, Gregory T.;Moore, Camille M.;Walter, Nicholas D.
• 通讯作者: Walter, Nicholas D.

MOVER approximated CV: A tool for quantifying precision in ratiometric droplet digital PCR assays.

• DOI: 10.1016/j.jpba.2022.114664
• 发表时间: 2022-04-01
• 期刊: Journal of pharmaceutical and biomedical analysis
• 影响因子: 3.4
• 作者: Dide-Agossou C;Rossmassler K;Reid J;Purohit J;Savic RM;Nahid P;Phillips PPJ;Moore CM;Walter ND
• 通讯作者: Walter ND