Translational approaches to improve understanding and outcome in Tuberculous meningitis

提高对结核性脑膜炎的理解和结果的转化方法

基本信息

批准号：
10755892
负责人：
Martin Alfons Gengenbacher
金额：
$ 70.31万
依托单位：
HACKENSACK UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-19 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10755892
关键词：
Adult Animal Model Antibiotics Aspirin Basic Science Biological Markers Biology Brain Brain Injuries Cells Cellular biology Central Nervous System Cerebrospinal Fluid Cessation of life Clinical Clinical Data Clinical Research Clinical Trials Collaborations Combined Antibiotics Coupled Data Death Rate Disease Disease Outcome Disease Progression Dose Drug Exposure Drug Interactions Drug Kinetics Ensure Funding Future Glutamates HIV Human Immune response Immunobiology Immunology In Vitro Individual Indoles Infection Inflammation Injury Institution Investigation Knowledge Lesion Linezolid Mass Spectrum Analysis Measures Meningeal Tuberculosis Metabolic Modeling Molecular Mycobacterium tuberculosis Nervous System Trauma Neurologic Oryctolagus cuniculus Outcome Output Participant Pathogenesis Pathway interactions Patients Penetration Pharmaceutical Preparations Pharmacodynamics Pharmacology Pharmacotherapy Phase Plasma Population Pre-Clinical Model Principal Investigator Propionic Acids Proteomics Publishing Regimen Rifampin Role Safety Sampling Signal Pathway Site South Africa Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Survivors Testing Therapeutic Intervention Tissues Toxic effect Translating Translational Research Tryptophan Tuberculosis Work antimicrobial blood-brain barrier crossing brain tissue clinical trial analysis defined contribution disability dosage drug candidate drug repurposing efficacy evaluation evidence base excitotoxicity experimental study gamma-Aminobutyric Acid immune modulating agents immunopathology improved in vivo in vivo magnetic resonance spectroscopy innovation insight laser capture microdissection mass spectrometric imaging metabolomics mortality multiple omics neurotoxic novel novel therapeutics pathogen patient population pharmacodynamic model pharmacokinetic model pharmacokinetics and pharmacodynamics phase III trial pre-clinical predictive marker programs protein biomarkers response standard of care therapeutic evaluation tool transcriptomics translational approach translational model translational research program treatment response tuberculosis drugs

项目摘要

ABSTRACT Tuberculous meningitis (TBM) arises when Mycobacterium tuberculosis (Mtb) crosses the blood-brain barrier (BBB), and is the most lethal and disabling form of tuberculosis (TB). In some patient populations, including HIV patients, TBM mortality approaches 50% despite therapy, and long-term disability is very common amongst survivors due to permanent brain injuries. These injuries are induced in large part by tissue damaging immune responses and by metabolic disturbance leading to neurotoxic and degenerative neurological damage. This project is based on our hypothesis that poor clinical outcomes in TBM are due to tissue damaging inflammation, the lack of adequate therapies that dampen counterproductive host responses, and inadequate antibiotic penetration into central nervous system (CNS) lesions. We propose an integrated program of translational and clinical research to develop and validate tools, biomarkers and models, which will help predict disease-induced disability, quantify drug penetration at the site of disease, characterize disease progression, and model response to therapy. The program combines multi- omic, pharmacokinetic and drug-drug interaction analyses of clinical trial samples, with investigations of pathogenesis, drug penetration at the site of disease, and testing of novel treatments in a rabbit model of TBM disease. The clinical -omics signatures will not only generate predictors of death and disability, but also guide optimization of the rabbit model. The project will draw from two separately funded Phase IIA and Phase III trials (LASER-TBM and INTENSE-TBM, respectively) in South Africa, evaluating the safety and efficacy of enhanced antimicrobial and host-directed therapy, including antibiotics approved for TB (high dose rifampicin added to standard of care) and repurposed drugs (linezolid and aspirin), for adults with TBM. We will use the optimized rabbit model of TBM to measure the CNS lesion penetration of TB-specific and repurposed antibiotics and of novel agents. If adequate CNS penetration is demonstrated, the pathogen- and host-directed activity of these drugs will be further evaluated in the rabbit model. Using these outputs, we will build a translational model integrating clinical and rabbit site-of-disease PK-PD data to define the contribution of therapeutic interventions on efficacy endpoints in clinical trials, and to define PK-PD targets for antitubercular therapy in TBM. The results of these integrated approaches will be forward-translated to propose evidence-based drug regimens with the potential to improve on death rate and neuro-disability. The principal investigators and their teams combine basic, translational and clinical research at four institutions with expertise in multi-omics analyses, pharmacology and immunobiology.

抽象的结核分枝杆菌（MTB）越过血脑验，结核性脑膜炎（TBM）出现屏障（BBB），是结核病（TB）最致命和残疾的形式。在某些患者人群中，包括艾滋病毒患者，尽管治疗疗法，TBM死亡率仍接近50％，而长期残疾非常普遍在由于永久性脑损伤而导致的幸存者中。这些伤害在很大程度上通过组织损害引起免疫反应和代谢障碍导致神经毒性和退化性神经系统损害。该项目基于我们的假设，即TBM中的临床结果不良是由于组织破坏炎症，缺乏足够的疗法来抑制适得其反的宿主反应，并且不足抗生素渗透到中枢神经系统（CNS）病变中。我们提出了一项综合计划的转化和临床研究计划，以开发和验证工具，生物标志物和模型将有助于预测疾病诱导的残疾，可以量化该部位的药物渗透率疾病，疾病进展的特征以及对治疗的模型反应。该程序结合了多种多样临床试验样本的OMIC，药代动力学和药物相互作用分析，并研究了发病机理，疾病部位的药物渗透以及在TBM的兔模型中对新治疗的测试疾病。临床 - 组的特征不仅会产生死亡和残疾的预测指标，而且还会指导兔模型的优化。该项目将从两个单独资助的IIA和III期试验中提取（分别激光-TBM和Intense-TBM）在南非，评估增强的安全性和功效抗菌和宿主指导的疗法，包括批准用于结核病的抗生素（高剂量利福平添加到针对患有TBM的成年人的护理标准和重新利用药物（LineZolid和阿司匹林）。我们将使用优化 TBM的兔模型，以测量TB特异性和再利用抗生素的中枢神经系统病变渗透和新颖的代理商。如果证明了足够的CNS穿透，则这些病原体和宿主指导的活性药物将在兔模型中进一步评估。使用这些输出，我们将建立一个翻译模型整合临床和兔子疾病的位点PK-PD数据，以定义治疗干预措施的贡献在临床试验中的功效终点上，并定义了TBM中抗结核疗法的PK-PD靶标。结果这些综合方法将被前进翻译，以提出基于证据的药物方案提高死亡率和神经可持续性的潜力。主要调查员及其团队结合了在多词分析中具有专业知识的四个机构的基础，转化和临床研究，药理学和免疫生物学。