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.

项目摘要/摘要

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