Elafin Therapy for Pulmonary Arterial Hypertension

Elafin 治疗肺动脉高压

• 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
• 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

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.

我们提出了一个TPPG周期II，该周期基于周期I的成功，以显示Elafin作为一个 逆转肺动脉高压（PAH）的治疗，呼吸机诱导新生儿肺损伤，并 肺移植排斥。这些条件中的每一个都可能是周期II的主题。但是，我们选择集中精力 自FDA以来，在PAH上，将孤儿毒品状态授予Elafin作为PAH的治疗 医疗需求。当前的疗法不会逆转或阻止肺血管的进行性闭塞 在PAH中导致临床恶化和肺移植的需求。在周期I期间，我们获得了 通过NIH-Smartt计划的帮助，资助非GLP药代动力学和毒理学研究，该研究表明 每天在大鼠中每天皮下给予Elafin的良好特征。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 即将与FDA举行的联合会议。 Proteo和Stanford之间的合同协议正在进行中 在第二周期的斯坦福大学与Elafin一起为研究人员发起的IND进行IND。项目1的目标是 因此，更好地了解为什么Elafin最有可能显示出临床功效。我们将 研究elafin在中性粒细胞功能中的作用以及与肺动脉内皮细胞的相互作用（PA EC）。源自诱导的多能干细胞的EC将作为天然PA EC的替代物进行研究 了解对Elafin的响应的基础，我们将定义Elafin的相互作用以识别新颖 该疗法的功能和潜在陷阱。与项目2和3和高级合作 蛋白质组学表型核心，我们将使用Cytof扩展我们在循环中发现的“ PAH签名” 细胞（PBMC）并研究了Elafin在体外修饰这种异常特征的程度 并在接受Elafin处理的受试者中。我们将使用MIBI并应用ABSEQ来确定 免疫细胞和嗜中性粒细胞，这些细胞被募集到肺周围的生态裂市场。项目2旨在解决 通过攻击异常和适应性的Elafin和Treg免疫疗法的潜在协同作用 PAH的免疫反应。在已知的PAH风险因素的背景下，Treg的颠覆功能 （雌性性别，BMPR2突变）在新型的肺动脉高压大鼠模型中进行了研究。 测试战略方法以扩大和改善Treg功能作为与Elafin的组合处理 或作为独立的PAH疗法。项目3的目标是利用I期临床试验 新斯坦福大学临床研究和翻译设施中的药代动力学和毒性终点 单位（CRTU）。在大鼠中进行的延长的180天GLP毒性和药代动力学研究将在一个小的之前 多中心II期临床试验的患者将纳入毒性，药代动力学和功效 端点。我们的TPPG翻译了数十年的基本机械研究，这些研究融合了弹性酶抑制， Elafin是一种有希望的PAH疗法，也使我们定位评估PAH的Treg免疫疗法。