Elafin Therapy for Pulmonary Arterial Hypertension

我们提出了TPG周期II，它建立在周期I的成功基础上，显示了Elafin作为一种 逆转新生儿肺动脉高压、呼吸机致肺损伤的治疗，以及 肺移植排斥反应。这些情况中的每一种都可能成为第二周期的主题。然而，我们选择关注 自从FDA将Elafin作为治疗PAH的孤儿药物授予Elafin作为紧急未满足的 医疗需要。目前的治疗方法不能逆转或阻止肺血管的进行性闭塞 在PAH中，导致临床恶化和肺移植的需要。在第一周期中，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的有利条件。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举行联席会议。Proteo和斯坦福之间的合同协议正在进行中 在第二周期中，在斯坦福大学用Elafin进行研究人员发起的临床试验的IND。项目1的目标是 因此，为了更好地了解Elafin为什么以及在谁身上最有可能显示临床疗效。我们会 探讨Elafin对中性粒细胞功能及与肺动脉内皮细胞(PA)相互作用的影响 EC)。诱导多能干细胞来源的EC将作为天然PA EC的替代品进行研究 了解对Elafin的响应性的基础，我们将定义Elafin的相互作用组以识别小说 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(PBMCs)，并研究Elafin在体外对这一异常信号的修饰程度 在接受Elafin治疗的受试者中。我们将使用MIBI和应用ABSEQ来确定生物 免疫细胞和中性粒细胞被招募到肺血管周围的壁龛。项目2旨在解决 Elafin和Treg通过攻击异常的先天和适应性免疫治疗的潜在协同作用 PAH中的免疫反应。在已知PAH危险因素的背景下Tregs的颠覆作用 (女性，BMPR2突变)在新的实验性大鼠肺动脉高压模型中进行了研究。 测试了战略方法，以扩大和改善Treg功能，作为Elafin的联合治疗 或者作为一种单独的PAH疗法。项目3的目标是进行一期临床试验，利用 斯坦福大学新临床研究和翻译中心设施中的药代动力学和毒性终点 单位(CRTU)。一项在大鼠身上进行的180天延长的GLP毒性和药代动力学研究将在小剂量 多中心II期临床试验，将包括毒性、药代动力学和疗效 终端。我们的TPPG翻译了数十年的基础机制研究，这些研究集中在弹性蛋白酶抑制上， 和Elafin作为一种有前景的PAH治疗方法，也为我们评估Treg免疫疗法治疗PAH奠定了基础。

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.