Elafin Therapy for Pulmonary Arterial Hypertension

Elafin 治疗肺动脉高压

基本信息

批准号：
9147499
负责人：
Marlene Rabinovitch
金额：
$ 179.1万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-17 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9147499
关键词：
Address Agreement Ancillary Study Animal Model Animals Antibodies BMPR2 gene Biological Assay Biological Markers Biology Blood Circulation Blood Vessels Cell Communication Cells Clinical Clinical Research Clinical Trials Collaborations Critical Pathways Cytometry Deterioration Disease Dose Drug Kinetics Elastases Elements Endothelial Cells Environment Estrogens European Female Functional disorder Funding Funding Agency Gender Gene Expression Genetic Genomics Goals Graft Rejection Grant Group Meetings Health Host Defense Human Immune Immunophenotyping Immunotherapy Impairment In Vitro Individual Industrialization Inflammation Inflammatory Intravenous Joints Label Laboratories Ligation Link Lung Lung Transplantation Mass Spectrum Analysis Mediating Medical Microscopy Modeling Molecular Molecular Abnormality Multiplexed Ion Beam Imaging Mutation Natural Immunity Nature Neutrophil Infiltration Newborn Infant Orphan Drugs PI3 gene Pathology Pathway interactions Patients Phase I Clinical Trials Phase II Clinical Trials Phenotype Positioning Attribute Predisposition Production Program Research Project Grants Proteins Proteomics Pulmonary Hypertension RNA-Protein Interaction Rattus Recombinants Regulatory T-Lymphocyte Research Infrastructure Research Personnel Risk Factors Role Sex Bias Signal Transduction Smooth Muscle Myocytes Surface Techniques Technology Testing Time Tissues Toxic effect Toxicology Training Translating Treatment Efficacy United States National Institutes of Health Ventilator-induced lung injury Work adaptive immune response adaptive immunity base behavioral study bone morphogenetic protein 2 clinical development clinical efficacy clinical translation combinatorial epigenome improved induced pluripotent stem cell meetings neutrophil new technology novel phase 2 study phase I trial phase II trial pre-clinical preclinical study programs pulmonary arterial hypertension receptor receptor function response subcutaneous success synergism training opportunity

项目摘要

We propose a TPPG Cycle II that builds on the success of Cycle I in showing pre-clinical efficacy of Elafin as a treatment to reverse pulmonary arterial hypertension (PAH), ventilator induced lung injury of the newborn, and lung transplant rejection. Each of these conditions could be the subject of Cycle II. However, we chose to focus on PAH since the FDA granted orphan drug status to Elafin as a treatment for PAH, as an urgent unmet medical need. Current therapies do not reverse or arrest the progressive obliteration of the lung blood vessels in PAH that results in clinical deterioration and the need for lung transplantation. During Cycle I, we obtained help through the NIH-SMARTT program, to fund non-GLP pharmacokinetic and toxicology studies that showed a favorable profile for daily subcutaneous administration of Elafin in rats. Under the guidance of NIH-SMARTT consultants, we worked with our industrial partner, Proteo, to prepare a preIND briefing document for our upcoming joint meeting with the FDA. A contractual agreement between Proteo and Stanford is underway to pursue an IND for investigator-initiated clinical trials with Elafin at Stanford in Cycle II. The goal of Project 1 is, therefore, to better understand why and in whom Elafin is most likely to show clinical efficacy. We will investigate the role of Elafin in neutrophil function and interaction with pulmonary arterial endothelial cells (PA EC). EC derived from induced pluripotent stem cells will be investigated as surrogates for native PA EC to understand the basis for responsivity to Elafin, and we will define the interactome of Elafin to identify novel functions and potential pitfalls of this therapy. In collaboration with Projects 2 and 3 and the Advanced Proteomic Phenotyping Core, we will use CyTOF to extend the `PAH signature' we have found in circulating cells (PBMCs) and to investigate the extent to which this abnormal signature is modified by Elafin both in vitro and in subjects being treated with Elafin. We will use MIBI and apply ABseq to determine the biology of immune cells and neutrophils that are recruited to the lung perivascular niche. Project 2 aims to address the potential synergy of Elafin and Treg immunotherapy by attacking both the abnormal innate and adaptive immune responses in PAH. The subverted function of Tregs in the context of known risk factors for PAH (female gender, BMPR2 mutation) is investigated in novel experimental rat models of pulmonary hypertension. Strategic approaches are tested to amplify and improve Treg function as a combinatorial treatment with Elafin or as a stand-alone PAH therapy. The objectives of Project 3 are to carry out a Phase I clinical trial utilizing pharmacokinetic and toxicity endpoints in the facilities of the new Stanford Clinical Research and Translation Unit (CRTU). An extended 180 day GLP toxicity and pharmacokinetic study in the rat will precede a small multi-center Phase II clinical trial in patients, that will incorporate toxicity, pharmacokinetic and efficacy endpoints. Our TPPG translates decades of basic mechanistic studies that converge on elastase inhibition, and Elafin as a promising PAH therapy and also positions us to evaluate Treg immunotherapy for PAH.

我们提出了 TPPG 周期 II，它建立在周期 I 的成功基础上，展示了 Elafin 作为一种药物的临床前功效。治疗逆转肺动脉高压（PAH）、呼吸机引起的新生儿肺损伤，以及肺移植排斥反应。这些条件中的每一个都可以成为第二周期的主题。然而我们选择专注自从 FDA 授予 Elafin 作为治疗 PAH 的孤儿药地位以来，PAH 一直是一个紧迫的未满足的问题医疗需要。目前的疗法不能逆转或阻止肺血管的进行性闭塞肺动脉高压（PAH）导致临床恶化并需要肺移植。在周期 I 期间，我们获得了通过 NIH-SMARTT 计划提供帮助，资助非 GLP 药代动力学和毒理学研究，这些研究表明对大鼠每日皮下注射 Elafin 具有良好的效果。在 NIH-SMARTT 的指导下顾问，我们与我们的工业合作伙伴 Proteo 合作，为我们的项目准备了 preIND 简报文件即将与 FDA 举行联席会议。 Proteo 和斯坦福大学之间的合同协议正在进行中在斯坦福大学第二周期中寻求研究者发起的 Elafin 临床试验 IND。项目 1 的目标是，因此，为了更好地了解 Elafin 为何以及在谁身上最有可能显示出临床疗效。我们将研究 Elafin 在中性粒细胞功能及其与肺动脉内皮细胞 (PA) 相互作用中的作用欧共体）。来自诱导多能干细胞的 EC 将作为天然 PA EC 的替代物进行研究了解对 Elafin 反应的基础，我们将定义 Elafin 的相互作用组来识别新颖的该疗法的功能和潜在缺陷。与项目 2 和 3 以及高级项目合作蛋白质组表型核心，我们将使用 CyTOF 来扩展我们在流通中发现的“PAH 特征” 细胞 (PBMC) 并研究 Elafin 在体外对这种异常特征的修改程度以及接受 Elafin 治疗的受试者。我们将使用 MIBI 并应用 ABseq 来确定免疫细胞和中性粒细胞被招募到肺血管周围生态位。项目2旨在解决 Elafin 和 Treg 免疫疗法通过攻击异常先天性和适应性的潜在协同作用 PAH 中的免疫反应。在已知的 PAH 危险因素背景下，Treg 的功能被颠覆（女性，BMPR2 突变）在新型肺动脉高压实验大鼠模型中进行了研究。作为与 Elafin 的组合治疗，测试了放大和改善 Treg 功能的战略方法或作为独立的 PAH 治疗。项目3的目标是利用新斯坦福临床研究和转化设施中的药代动力学和毒性终点单位（CRTU）。在进行小型研究之前，将在大鼠中进行一项为期 180 天的 GLP 毒性和药代动力学研究。在患者中进行的多中心 II 期临床试验，将综合毒性、药代动力学和疗效端点。我们的 TPPG 转化了几十年来集中于弹性蛋白酶抑制的基本机制研究， Elafin 是一种有前途的 PAH 疗法，也使我们能够评估 PAH 的 Treg 免疫疗法。