An additive solution to expand the lung transplant organ pool

项目总结 肺移植领域的主要挑战是健康供体肺(移植物)的可用性低和 移植后对供体肺的损害。这些症状是由于炎症和氧化损伤引起的。 在嫁接储存期内。在用于提高肺可利用度和 移植的结果是保存时间短(包括&lt；3小时，灌流保存，即体外肺 灌流或EVLP循环、低温储存和各种抗氧化剂溶液的使用)和 移植后的免疫抑制治疗。其中，仅EVLP一家就显示出了希望；然而，它是成本- 令人望而却步，而且在肺采集点往往无法获得。然而，免疫抑制疗法 部分有效对移植受者来说是虚弱的。 Peroxitech LLC建议使用另一种策略来阻止最早的信号事件 在肺储存期间被触发，进而导致炎症和损伤。来自Chatterjee小组的工作 研究表明，肺血管壁对与肺储存相关的血流停止的反应是通过 激活内皮细胞信号级联导致NADPH氧化酶2(NOX2)的激活和反应性 氧气(ROS)的产生。该小组还报告了磷脂酶A2(PLA2)的活性。 过氧化还蛋白6在NOX2的激活中起着至关重要的作用。最近，Peroxitech发现了一种九种氨基酸 多肽序列(PIP-2)，可阻断Prdx6的PLA2活性，从而降低NOX2的激活和 ROS生产。初步数据显示，小鼠肺中储存的9种氨基酸多肽明显 降低了ROS的产量。肺中ROS的产生是公认的，可以引起炎症和 作为先天(中性粒细胞或中性粒细胞)募集信号的抗原提呈级联 中性粒细胞)和获得性免疫细胞(T淋巴细胞)。PMN附着在血管壁上。 新移植的肺(移植物)在激活T细胞的同时，迁移和释放氧化剂对移植物造成损伤。 淋巴细胞驱动移植物组织的溶解。Peroxitech建议通过阻断供体肺的 与PIP-2(体外)一起储存期间的信号，使PMN募集和T细胞激活(两者均为 它们依赖于ROS)在移植后被最小化。因此，这将评估PIP-2作为肺保存 解决方案。我们将在目标1)评估PIP-2制剂在供体肺保护中的有效性， 保存时间和目的2)评价PIP-2作为保存液在小鼠肺移植中的作用 结果。如果获得的数据显示在肺存储期间使用PIP-2导致显著减少 炎症、损伤和肺功能的改善，移植后，我们将能够进入第二阶段 在分离的人类供体肺中对这种药物进行全面的临床和分析评估，最终用于FDA 批准。

PROJECT SUMMARY Major challenges in the field of lung transplantation are the low availability of healthy donor lungs (graft) and the damage to donor lungs post-transplant. These arise due to inflammation and oxidative damage initiated during the graft storage period. Among the multiple strategies employed to improve lung availability and transplant outcome are short storage times (comprising of < 3 h, storage under perfusion i.e. ex vivo lung perfusion or EVLP circuit, hypothermic storage, and the use of various antioxidant solutions) and immunosuppression therapy post-transplant. Of these, EVLP alone shows promise; however it is cost- prohibitive and often unavailable at the point of site of lung procurement. Immunosuppressive therapy, though partially effective is debilitating for the transplant recipient. Peroxitech LLC proposes to use an alternate strategy of blocking the earliest signaling events that are triggered during lung storage and that in turn lead to inflammation and injury. Work from the Chatterjee group has shown that pulmonary vascular wall responds to stop of blood flow associated with lung storage by activating an endothelial signaling cascade that leads to activation of NADPH oxidase 2 (NOX2) and reactive oxygen species (ROS) production. This group also reported that the phospholipase A2 (PLA2) activity of the enzyme Peroxiredoxin 6 is crucial in NOX2 activation. Recently, Peroxitech discovered a nine amino-acid peptide sequence (PIP-2) that can block the PLA2 activity of Prdx6 and thus diminish NOX2 activation and ROS production. Preliminary data shows that murine lungs stored in the 9 peptide aminoacid significantly reduced ROS production. ROS generation in lungs is well established to cause activation of inflammation and antigen presentation cascades which are signals for recruitment of innate (polymorphonuclear neutrophils or PMN) and adaptive immune cells (T lymphocytes) from the recipient. PMN adhere to the vessel wall of the newly transplanted lung (graft), transmigrate and release oxidants causing injury to the graft while activated T- lymphocytes drive lysis of the graft tissue. Peroxitech proposes to pre-“treat” donor lungs by blocking the signals during storage with PIP-2 (outside the body) such that PMN recruitment and T cell activation (both of which are ROS dependent) after transplant, is minimized. For this will evaluate PIP-2 as a lung preservation solution. We will in Aim 1) Evaluate PIP-2 formulations for effectivity in donor lung protection with increasing storage times and Aim 2) Evaluate the effect of PIP-2 as a preservation solution in murine lung transplant outcomes. If data obtained show that PIP-2 usage during lung storage leads to a significant reduction in inflammation, injury and an improved lung function, post-transplant, we will be enabled to proceed to Phase II with a full clinical and analytical evaluation of this agent in isolated human donor lungs, for an eventual FDA approval.