Novel Therapeutic Approaches in IPF

IPF 的新颖治疗方法

• 批准号: 6914736
• 负责人: Fernando J Martinez
• 金额: $ 29.26万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6914736
• 关键词: acetylcysteine; antiinflammatory agents; azathioprine; chimeric proteins; clinical research; clinical trials; combination chemotherapy; cooperative study; exotoxins; human subject; human therapy evaluation; inhalation drug administration; interleukin 13; patient oriented research; prednisone; pulmonary fibrosis /granuloma; respiratory disorder chemotherapy

DESCRIPTION (provided by applicant): The idiopathic interstitial pneumonias (IIP) represent a group of acute and chronic diffuse parenchymal lung diseases of unknown etiology. Idiopathic pulmonary fibrosis (IPF) is the most deadly and common type of IIP. As our understanding IPF evolves, it is evident that IPF is a heterogeneous disease. We previously demonstrated that multiple histopathologic patterns of IIP often exist within the same patient. Similarly, the same patient may exhibit areas of both inflammation and fibrosis, depending on the area of lung examined. There is no cure for IPF. The current recommended treatment regimen is anti-inflammatory and combines a cytotoxic agent (such as azathioprine or cyclophosphamide) with prednisone (American Thoracic Society, 2000). Although some patients seem to respond or stabilize, there are few rigorous data clearly elucidating the efficacy and safety of this regimen for patients diagnosed with IPF using current diagnostic guidelines. It is plausible that the failure of current therapeutic approaches reflects the lack of a simultaneous, multi-faceted assault against multiple biologically plausible targets involved in the pathogenesis of IPF. We hypothesize that novel therapies engineered to exploit specific pathophysiologic features of IPF will prove to have the greatest therapeutic success. With these concepts in mind, we propose two novel therapeutic trials for previously untreated patients with IPF. IPF is characterized by the overproduction of pro-fibrotic leukotrienes and underproduction of anti-inflammatory PGE2. Our first protocol compares the combination of two agents selected to correct this imbalance: zileuton plus N-acetyl cysteine versus standard therapy with azathioprine plus prednisone. IPF is also characterized by increased expression of the profibrotic cytokine IL-13 receptor compared to other types of IIP. Our second protocol advantages this observation by utilizing an aerosolized fusion protein comprised of human IL-13 and a mutated form of Pseudomonas exotoxin. Internalization of this fusion protein results in cellular apoptosis. Both trials are randomized, double-blind, placebo-controlled trials. The primary endpoint in each trial is a combination of death or decline in FVC of >10%. Secondary endpoints include safety, changes in pulmonary function, quality of life, dyspnea, six-minute walk distance, change in saturation during a six-minute walk test, and respiratory hospitalizations. These protocols will define the role of standard therapy, test the efficacy of targeted combination therapy, and explore the promise of a novel approach to the design and delivery of therapeutic agents for IPF. (End of Abstract)

描述（由申请人提供）： 特发性间质性肺炎（IIP）是一组病因不明的急性和慢性弥漫性肺实质疾病。 特发性肺纤维化（IPF）是最致命和最常见的IIP类型。 随着我们对IPF的理解不断发展，很明显，IPF是一种异质性疾病。 我们以前证明，多种组织病理学模式的IIP往往存在于同一个病人。 同样，根据检查的肺面积，同一患者可能同时表现出炎症和纤维化。 IPF无法治愈。 目前推荐的治疗方案是抗炎，并结合细胞毒性药物（如硫唑嘌呤或环磷酰胺）与泼尼松（美国胸科学会，2000）。 尽管一些患者似乎缓解或稳定，但很少有严格的数据明确阐明该方案对使用当前诊断指南诊断为IPF的患者的疗效和安全性。 目前治疗方法的失败似乎反映了缺乏对IPF发病机制中涉及的多种生物学合理靶点的同时、多方面攻击。 我们假设，旨在利用IPF特定病理生理学特征的新型治疗方法将证明具有最大的治疗成功率。 考虑到这些概念，我们提出了两项针对既往未经治疗的IPF患者的新型治疗试验。 IPF的特征在于促纤维化白三烯的过度产生和抗炎性PGE 2的产生不足。 我们的第一个方案比较了两种药物的组合，以纠正这种不平衡：齐留通加N-乙酰半胱氨酸与标准治疗硫唑嘌呤加泼尼松。 与其他类型的IIP相比，IPF的特征还在于促纤维化细胞因子IL-13受体的表达增加。 我们的第二个方案通过利用由人IL-13和突变形式的假单胞菌外毒素组成的气溶胶化融合蛋白来使这一观察有利。 这种融合蛋白的内化导致细胞凋亡。 两项试验均为随机、双盲、安慰剂对照试验。 每项试验的主要终点是死亡或FVC下降> 10%的组合。 次要终点包括安全性、肺功能变化、生活质量、呼吸困难、6分钟步行距离、6分钟步行试验期间饱和度变化和呼吸系统住院。 这些方案将定义标准治疗的作用，测试靶向联合治疗的疗效，并探索IPF治疗药物设计和给药新方法的前景。 (End摘要）