Refanalin for lung preservation and transplantation

描述（由申请人提供）：肺移植是终末期肺病患者唯一有效的治疗方式。缺血再灌注损伤，与回收，存储和肺移植是一个主要的免疫无关的因素，对早期移植功能，移植物的活力和受体发病率和死亡率产生不利影响。边缘供体肺甚至更容易受到缺血-再灌注损伤，并且经常移植失败。分散因子/肝细胞生长因子在肺缺血-再灌注损伤的情况下具有显著的保护活性，此外，有利于肺上皮修复和再生。然而，其临床应用受到与其给药相关的后勤困难的限制。在我们的I期项目中，我们已经确定了Refanalin，一种有机小分子分散因子/肝细胞生长因子模拟物，可改善继发于缺血再灌注损伤的肺功能，减轻肺上皮死亡并促进上皮再生。在肺冷保存和移植的临床前模型中，Refanalin治疗减少了X线肺泡浸润，改善了肺功能并保留了肺微结构。目前的II期研究对Refanalin在临床相关肺移植模型中的疗效进行了深入评价。通过减轻同种异体移植物功能障碍和预防移植物衰竭，Refanalin可以降低受体发病率和死亡率。通过减轻边缘肺的缺血-再灌注损伤，Refanalin可以挽救否则将被丢弃的器官，并增加供体库。公共卫生相关性：可添加到肺保存溶液中并施用于移植物受体的小分子细胞保护剂在肺和其他实体器官移植中具有显著的临床潜力。

DESCRIPTION (provided by applicant): Lung transplantation is the only effective treatment modality for patients with end-stage lung disease. Ischemia-reperfusion injury, associated with the retrieval, storage and transplantation of the lung is a major immune-independent factor adversely affecting early graft function, graft viability and recipient morbidity and mortality. Marginal donor lungs, are even more susceptible to ischemia-reperfusion injury, and often fail transplantation. Scatter factor/hepatocyte growth factor has significant protective activity in the setting of pulmonary ischemia-reperfusion injury and additionally, favors pulmonary epithelial repair and regeneration. However its clinical use is limited by the logistical difficulties associated with its administration. During our Phase I program, we have identified Refanalin, an organic small molecule scatter factor/hepatocyte growth factor mimetic that improves lung function secondary to ischemia-reperfusion injury, attenuates pulmonary epithelial death and promotes epithelial regeneration. In a preclinical model of lung cold preservation and transplantation, Refanalin treatment reduced roentgenographic alveolar infiltration, improved pulmonary function and preserved pulmonary microarchitecture. The present Phase II makes an in-depth evaluation of Refanalin efficacy in clinically relevant models of lung transplantation. By attenuating allograft dysfunction and preventing allograft failure, Refanalin can reduce recipient morbidity and mortality. By attenuating ischemia- reperfusion injury in the marginal lung, Refanalin can salvage an otherwise discarded organ, and increase the donor pool. PUBLIC HEALTH RELEVANCE: A small molecule cytoprotective that can be added to the lung preservation solution and administered to graft recipient has significant clinical potential in lung and other solid organ transplantation.