Refanalin for lung preservation and transplantation

描述（由申请人提供）：肺移植已成为大多数终末期肺部疾病（包括肺气肿、囊性纤维化和特发性肺纤维化）的主要治疗方法。然而，对合适供体肺的需求不断增加，远远超过了可用器官的数量，部分原因是肺对缺血非常敏感。轻度至重度缺血再灌注损伤是肺移植受者常见的并发症。目前的保存液（例如，低钾右旋糖酐葡萄糖，LPDG）可靠地将收获的肺保存4至8小时，并且没有利用对细胞凋亡理解的最新进展来最小化保存期间的肺损伤。肝细胞生长因子（HGF），也称为分散因子（SF），是一种多效性生长因子，主要通过其促有丝分裂和抗凋亡活性诱导不同细胞类型的活化和增殖。在保存液中添加重组SF/HGF可增强移植后器官功能。虽然SF/HGF作为蛋白质疗法的施用具有治疗肺功能障碍的潜力，但其可行性受到与溶液中蛋白质的固有不稳定性和有限的组织半衰期相关的问题的限制。使用药物发现引擎，包括噬菌体展示，三维分子建模，我们已经确定了Refanalin，一种有机小分子SF/HGF模拟物，可以作为改善肺功能障碍和减少移植后早期移植物衰竭的重要疗法。本研究的目的是使用我们的SF/HGF模拟物作为当前保存溶液的添加剂，将肺移植的肺保存时间延长至12-18小时。初步数据表明，Refanalin在体外保护细胞凋亡/坏死细胞死亡，并在体内保护器官功能。此外，在我们的动物模型中，Refanalin可以提高肝和肾移植的成功率。本研究旨在通过动物模型研究Refanalin对肺移植缺血诱导的细胞凋亡/坏死的保护作用。肺移植已成为治疗包括肺气肿、囊性纤维化和特发性肺纤维化在内的大多数终末期肺部疾病的主要手段。一种能延长供体肺保存时间的小分子药物将具有巨大的临床效益。

DESCRIPTION (provided by applicant): Lung transplantation has become the mainstay of therapy for most end stage lung diseases including pulmonary emphysema, cystic fibrosis, and idiopathic pulmonary fibrosis. However, increasing demand for suitable donor lungs far exceeds the number of available organs, in part because the lung is exquisitely sensitive to ischemia. Mild to severe ischemia-reperfusion injury is a frequent complication in lung transplant recipients. Current preservation fluids (e.g., low-potassium dextran glucose, LPDG) reliably preserve harvested lungs for 4 to 8hr and do not exploit recent advances in understanding of apoptosis to minimize lung injury during preservation. Hepatocyte growth factor (HGF), also known as scatter factor (SF), is a pleiotropic growth factor that induces the activation and proliferation of diverse cell types, largely through its mitogenic and anti-apoptotic activities. Addition of recombinant SF/HGF to the preservation solution enhances post-transplant organ function. While administration of SF/HGF as protein therapy has potential for the treatment of lung dysfunction, its feasibility is limited by issues relating to inherent instability of proteins in solution and limited tissue half-life. Using a drug discovery engine that includes phage display, 3-dimensional molecular modeling, we have identified Refanalin, an organic small molecule SF/HGF mimetic that could serve as important therapeutics in ameliorating lung dysfunction and reducing early graft failure following transplantation. The objective of our study is to extend the lung preservation time up to 12-18 hr for lung transplantation using our lead SF/HGF mimetic as an additive to current preservation solutions. Preliminary data indicate that Refanalin protects against apoptotic/necrotic cell death in vitro and preserves organ function in vivo. In addition, Refanalin can improve success rate in liver and kidney transplantation in our animal models. The proposed work is designed to identify a strategy to determine the protective effects of Refanalin against ischemia-induced apoptosis/necrosis in lung transplantation in an animal model. Lung transplantation has become the mainstay of therapy for most end stage lung diseases including pulmonary emphysema, cystic fibrosis, and idiopathic pulmonary fibrosis. A small- molecule drug that increases the preservation time of donor lungs will have tremendous clinical benefits.