An additive solution to expand the lung transplant organ pool

扩大肺移植器官库的附加解决方案

基本信息

批准号：
10480375
负责人：
SHAMPA CHATTERJEE
金额：
$ 29.99万
依托单位：
PEROXITECH, LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-20 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10480375
关键词：
Adherence Amino Acids Antigen Presentation Antioxidants Blood Circulation Blood Vessels Blood flow Cell Death Cells Clinical Collaborations Cytolysis Data Endothelium Evaluation Event Formulation Generations Goals High Resolution Computed Tomography Hour Human Immune Immune system Inflammation Inflammatory Injury Lead Lung Lung Transplantation Modeling Monitor Mus NADPH Oxidase Neutrophil Infiltration Organ Transplantation Outcome Oxidants Pennsylvania Peptides Perfusion Permeability Phase Phospholipase Phospholipase A2 Pilot Projects Production Property Reactive Oxygen Species Reporting Signal Transduction Site Small Business Technology Transfer Research Structure Structure of parenchyma of lung T-Cell Activation T-Lymphocyte Therapeutic immunosuppression Time Tissue Grafts Transplant Recipients Transplantation Transplantation Surgery Universities Work clinical practice cost efficacy evaluation enzyme activity immunoregulation improved in vivo Model injured lung injury lung preservation neutrophil novel oxidative damage peroxiredoxin phase 1 study post-transplant preservation prevent protein aminoacid sequence pulmonary function recruit transplant model

项目摘要

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.

项目概要肺移植领域的主要挑战是健康供体肺（移植物）的可用性低以及移植后供体肺的损伤是由于炎症和氧化损伤引起的。在移植物储存期间采用多种策略来提高肺的可用性和移植结果是储存时间短（包括 < 3 小时，灌注储存，即离体肺）灌注或 EVLP 回路、低温储存以及使用各种抗氧化剂溶液）和其中，EVLP 本身就有希望，但其成本较高。然而，在肺部获取部位却是令人望而却步且常常无法获得的。部分有效会使移植受者变得虚弱。 Peroxitech LLC 建议使用另一种策略来阻止最早的信号事件肺部储存期间触发，进而导致炎症和损伤。已经表明，肺血管壁通过以下方式对与肺储存相关的血流停止做出反应：激活内皮信号级联，导致 NADPH 氧化酶 2 (NOX2) 的激活和反应该小组还报道了磷脂酶 A2 (PLA2) 的活性。 Peroxiredoxin 6 酶对于 NOX2 激活至关重要。最近，Peroxitech 发现了九种氨基酸。肽序列（PIP-2）可以阻断 Prdx6 的 PLA2 活性，从而减少 NOX2 的激活和初步数据显示，小鼠肺中储存的 9 肽氨基酸显着增加。肺部 ROS 产生减少已被证实会导致炎症和炎症的激活。抗原呈递级联，是招募先天性（多形核中性粒细胞或 PMN）和来自受体的适应性免疫细胞（T 淋巴细胞）粘附在血管壁上。新移植的肺（移植物），迁移并释放氧化剂，在激活 T- 时对移植物造成损伤 Peroxitech 提出通过阻断淋巴细胞驱动移植组织裂解来预“治疗”供体肺。在用 PIP-2（体外）储存期间发出信号，使得 PMN 募集和 T 细胞激活（两者均移植后，ROS 依赖性）被最小化，因为这将评估 PIP-2 作为肺保存的作用。我们将在目标 1) 中评估 PIP-2 制剂在供体肺保护方面的有效性。储存时间和目的 2) 评估 PIP-2 作为小鼠肺移植保存液的效果如果获得的数据表明肺储存过程中 PIP-2 的使用会导致肺储存中 PIP-2 的显着减少。炎症、损伤和肺功能改善，移植后，我们将能够进入第二阶段对这种药物在分离的人类供体肺中进行全面的临床和分析评估，以最终获得 FDA 批准赞同。