Pathogenesis-Based Diagnostics and Pharmacotherapeutics for PAP

基于 PAP 发病机制的诊断和药物治疗

• 批准号: 10153849
• 负责人: Bruce C Trapnell
• 金额: $ 39.75万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153849
• 关键词: Acids; Alveolar; Alveolar Macrophages; Autoantibodies; Autoimmune; Automobile Driving; Biochemical; Biological Assay; Biological Markers; Biopsy; Blood; Blood Tests; Bronchoalveolar Lavage; Child; Cholesterol; Clinical; Clinical Paths; Clinical Trials; Colony-Stimulating Factor Therapy; Computer Analysis; Computer software; Data; Densitometry; Detection; Development; Diagnosis; Diagnostic; Diagnostic Reagent Kits; Diagnostic tests; Disease; Dose; Double-Blind Method; Drug Kinetics; Dyspnea; Excision; FDA approved; Funding; Future; Goals; Gold; Granulocyte-Macrophage Colony-Stimulating Factor; Homeostasis; Human; Inhalation; Kinetics; Knowledge; Laboratories; Lead; Letters; Literature; Low Prevalence; Lung; Lung diseases; Measurement; Measures; Mediating; Mediator of activation protein; Medical; Methods; Mission; Monitor; Mus; Outcome Measure; Outcomes Research; Oxygen; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacotherapy; Physicians; Physiological; Placebos; Predictive Value; Prevalence; Procedures; Public Health; Publishing; Pulmonary Alveolar Proteinosis; Quality of life; Radiology Specialty; Randomized; Registries; Reporting; Research; Respiratory Failure; Role; STAT5B gene; Safety; Scanning; Self Administration; Serum; Severities; Severity of illness; Signal Transduction; Specimen; Spottings; Stat5 protein; Syndrome; Techniques; Testing; Therapeutic; Therapy trial; Transplantation; United States National Institutes of Health; Validation; Woman; X-Ray Computed Tomography; accurate diagnosis; autoimmune pathogenesis; base; chest computed tomography; clinical development; design; effective therapy; factor A; gene complementation; health care delivery; improved; induced pluripotent stem cell; macrophage; men; novel; patient population; phase III trial; predictive test; primary endpoint; programs; pulmonary function; rapid diagnosis; research clinical testing; response; surfactant; treatment response; volunteer

ABSTRACT Despite our vastly improved understanding of pulmonary alveolar proteinosis (PAP) – a syndrome of surfactant accumulation and respiratory failure that occurs in multiple diseases; clinically, PAP is usually evaluated using methods (e.g., lung biopsy) unable to identify the PAP-causing disease and no drug is FDA-approved to treat it. One PAP-causing disease, autoimmune PAP (aPAP), is mediated by GM-CSF autoantibodies (GMAbs) and accounts for more than 90% of all cases. Importantly, while multiple clinical trials and an increasing of reports in the medical literature document the efficacy, safety and tolerability of inhaled GM-CSF therapy of aPAP, the use of outcome measures not yet validated in this patient population is a major barrier to regulatory approval. Low prevalence, underuse of effective diagnostics (leading to misdiagnosis and under-detection), and little knowledge of the kinetics by which GM-CSF regulates surfactant clearance by AMs comprise additional hurdles to pharmacotherapeutic development. In the prior funding periods, we developed a panel of pathogenesis-based blood tests including one – the Serum GMAb Test – that is 100% sensitive and specific for aPAP and is now the ‘gold standard’ for aPAP diagnosis. We also developed a dried blood spot card (DBSC) version of this test – the DBSC GMAb Test – and validated it in the laboratory against the Serum GMAb Test. Another test – the EC50-GM-CSF Signaling Test – identifies the amount of exogenous GM-CSF that must be added to heparinized blood (aPAP or control) to stimulate GM-CSF signaling. Finally, we found that serum cholestenoic acid and automated computer analysis of chest CT scans (using CALIPER software) can be used to measure disease severity and treatment responses in aPAP patients. We plan to test the following central hypothesis: mediators driving the pathogenesis of aPAP provide the basis for outstanding tests for diagnosis of aPAP, therapeutic GM-CSF dose-prediction, disease severity monitoring, and treatment response measurement. This hypothesis is strongly supported by our Preliminary Data. Further, the feasibility of the proposed research is increased by the existence of clinical specimens, data, and CT scans from a recently completed large (138 aPAP patient) randomized, double-blinded, placebo controlled clinical GM-CSF therapy trial, which are available to us. In Aim 1 we will evaluate DBSC-GMAb test kit for diagnosis of aPAP and EC50- GM-CSF Test for predicting the dose of GM-CSF patients will require as therapy of aPAP. In Aim 2, we will determine the kinetics by which GM-CSF regulates cholesterol (and surfactant) clearance by AMs and the role of ABCG1 and STAT5 in this mechanism. In Aim 3, we will evaluate several pathogenesis-related biochemical and radiological outcome measures of PAP disease severity and treatment responses. Expected results will validate a new test to accelerate and improve the diagnosis of aPAP, evaluate a test to determine the GM-CSF dose patients require as therapy aPAP, determine if GM-CSF therapy should be administered daily or on alternating weeks, and validate new outcome measures of lung disease and treatment responses in aPAP. These expected results are anticipated to have significant positive impact because they are expected to lead to improved healthcare delivery by practicing physicians, improve the quality of life for people living with PAP, and accelerate the pharmacotherapeutic development of GM-CSF as a new treatment for aPAP patients.

抽象的 尽管我们对肺泡蛋白沉积症（PAP）——一种表面活性剂综合征的认识有了很大的提高 多种疾病发生的蓄积和呼吸衰竭，临床上通常采用以下方法进行评估： （例如，肺活检）无法识别引起 PAP 的疾病，并且 FDA 还没有批准治疗一种引起 PAP 的疾病。 自身免疫性 PAP (aPAP) 疾病由 GM-CSF 自身抗体 (GMAb) 介导，占 90% 以上 重要的是，虽然多项临床试验和医学文献中越来越多的报告记录了这一点。 吸入 GM-CSF 治疗 aPAP 的有效性、安全性和耐受性，使用尚未在 这一患者群体是监管部门批准的主要障碍。患病率低，有效诊断方法使用不足。 （导致误诊和检测不足），并且对 GM-CSF 调节表面活性剂的动力学知之甚少 AM 的批准对药物治疗的开发构成了额外的障碍。 开发了一系列基于发病机制的血液测试，其中一项是血清 GMAb 测试，该测试具有 100% 的敏感性，并且 专门针对 aPAP，现已成为 aPAP 诊断的“金标准” 我们还开发了干血斑卡 (DBSC)。 该测试的版本 - DBSC GMAb 测试 - 并在实验室中针对血清 GMAb 测试进行了验证。 测试 – EC50-GM-CSF 信号测试 – 确定必须添加到肝素化的外源 GM-CSF 的量 血液（aPAP或对照）刺激GM-CSF信号最后，我们发现血清胆烯酸和自动化。 胸部 CT 扫描的计算机分析（使用 CALIPER 软件）可用于测量疾病严重程度和治疗 我们计划检验以下中心假设：驱动 aPAP 发病机制的介质。 aPAP 为诊断 aPAP、治疗性 GM-CSF 剂量预测、疾病严重程度等出色的测试提供了基础 我们的初步数据强烈支持这一假设。 此外，临床标本、数据和 CT 扫描的存在增加了拟议研究的可行性 来自最近完成的大型（138 名 aPAP 患者）随机、双盲、安慰剂对照临床 GM-CSF 治疗试验，在目标 1 中，我们将评估用于诊断 aPAP 和 EC50 的 DBSC-GMAb 检测试剂盒。 GM-CSF 测试用于预测 GM-CSF 患者作为 aPAP 治疗所需的剂量。在目标 2 中，我们将确定 aPAP 治疗所需的剂量。 GM-CSF 通过 AM 调节胆固醇（和表面活性剂）清除的动力学以及 ABCG1 和 STAT5 在 在目标 3 中，我们将评估几种与发病机制相关的生化和放射学结果指标。 预期结果将验证一项新的测试，以加速和改善 PAP 疾病的严重程度和治疗反应。 诊断 aPAP，评估测试以确定患者治疗 aPAP 所需的 GM-CSF 剂量，确定 GM-CSF 是否 治疗应每天或每隔几周进行一次，并验证肺部疾病和疾病的新结果指标 aPAP 中的治疗反应预计会产生显着的积极影响，因为它们是 预计将改善执业医生的医疗保健服务，提高人们的生活质量 与 PAP 合作，并加速 GM-CSF 作为 aPAP 患者新疗法的药物治疗开发。