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.

抽象的当结核分枝杆菌 (Mtb) 穿过血脑时，就会出现结核性脑膜炎 (TBM) 屏障（BBB），是最致命和最致残的结核病（TB）形式。在一些患者群体中，包括 HIV 患者在内，尽管进行了治疗，TBM 死亡率仍接近 50%，而且长期残疾也很常见由于永久性脑损伤的幸存者。这些损伤很大程度上是由组织损伤引起的免疫反应和代谢紊乱导致神经毒性和退行性神经损伤。该项目基于我们的假设，即 TBM 临床效果不佳是由于组织损伤造成的炎症、缺乏抑制适得其反的宿主反应的适当疗法以及不充分的治疗抗生素渗透到中枢神经系统（CNS）病变中。我们提出了一个转化和临床研究的综合计划来开发和验证工具，生物标志物和模型，这将有助于预测疾病引起的残疾，量化现场的药物渗透疾病的特征、疾病进展的特征以及对治疗的模型反应。该方案结合了多对临床试验样本进行组学、药代动力学和药物相互作用分析，并进行以下研究兔 TBM 模型的发病机制、疾病部位的药物渗透以及新疗法的测试疾病。临床组学特征不仅可以产生死亡和残疾的预测因子，还可以指导兔子模型的优化。该项目将来自两项单独资助的 IIA 期和 III 期试验（分别为激光 TBM 和密集 TBM）在南非，评估增强型 TBM 的安全性和有效性抗菌药物和针对宿主的治疗，包括批准用于结核病的抗生素（高剂量利福平添加到护理标准）和重新利用药物（利奈唑胺和阿司匹林），用于患有 TBM 的成人。我们将使用优化后的兔 TBM 模型，用于测量结核病特异性和重新用途抗生素的中枢神经系统病变渗透性新颖的代理。如果证明有足够的中枢神经系统渗透，这些病原体和宿主的定向活性药物将在兔子模型中进一步评估。使用这些输出，我们将构建一个翻译模型整合临床和兔子疾病部位 PK-PD 数据来确定治疗干预的贡献临床试验中的疗效终点，并确定 TBM 抗结核治疗的 PK-PD 目标。结果这些综合方法将向前转化，以提出基于证据的药物治疗方案降低死亡率和神经功能障碍的潜力。主要研究人员及其团队结合在一起四个具有多组学分析、药理学专业知识的机构进行基础、转化和临床研究和免疫生物学。