Elafin Therapy for Pulmonary Arterial Hypertension

我们提出了TPPG周期II，该周期II建立在周期I成功显示Elafin作为一种抗抑郁药的临床前疗效的基础上。 治疗以逆转肺动脉高压（PAH）、呼吸机诱导的新生儿肺损伤，以及 肺移植排斥反应这些条件中的每一个都可以是第二周期的主题。然而，我们选择专注于 自从FDA授予Elafin孤儿药地位作为PAH治疗以来， 医疗需求。目前的治疗不能逆转或阻止肺血管的进行性闭塞 在PAH中，导致临床恶化和需要肺移植。在第一周期，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， 大鼠每日皮下注射Elafin的有利特征。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 与FDA的联合会议。Proteo和斯坦福大学之间的合同协议正在进行中， 在斯坦福大学进行第二周期Elafin的药物启动临床试验IND。项目1的目标是， 因此，为了更好地了解为什么和谁Elafin最有可能显示临床疗效。我们将 研究Elafin对中性粒细胞功能的影响及其与肺动脉内皮细胞的相互作用 EC）。将研究来源于诱导多能干细胞的EC作为天然PA EC的替代物， 了解对Elafin的反应性的基础，我们将定义Elafin的相互作用组，以识别新的 这种疗法的功能和潜在的陷阱。与项目2和3以及高级 蛋白质组学表型核心，我们将使用CyTOF来扩展我们在循环中发现的“PAH签名”， 细胞（PBMC），并研究Elafin在体外对这种异常特征进行修饰的程度， 以及正在接受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募集到肺血管周围小生境。项目2旨在解决 Elafin和Treg免疫疗法通过攻击异常的先天性和适应性两者的潜在协同作用 PAH的免疫反应。在已知PAH风险因素的背景下，TdR的功能被破坏 （雌性，BMPR 2突变）在肺动脉高压的新实验大鼠模型中进行研究。 测试策略方法以扩增和改善Treg功能，作为与Elafin的组合治疗 或作为独立PAH治疗。项目3的目标是进行I期临床试验， 在新的斯坦福大学临床研究和翻译机构中进行药代动力学和毒性终点研究 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小规模的 在患者中开展的多中心II期临床试验，将纳入毒性、药代动力学和疗效 端点。我们的TPPG翻译了几十年的基本机制研究，这些研究集中在弹性蛋白酶抑制， 和Elafin作为一种有前途的PAH治疗，也使我们能够评估Treg免疫治疗PAH。

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.