A Therapeutic for Radiation Induced Lung Injury

描述（由申请人提供）：核事故和恐怖主义是造成大规模伤亡的严重威胁。在辐射事件中，许多人接受不均匀的全身或局部照射。由于恐怖活动而暴露于电离辐射的风险可能对成千上万人造成急性伤害和长期不利的健康影响。肺是对放射性更敏感的器官之一，吸入大量放射性核素会产生一系列严重的功能和形态变化，包括放射性肺炎和肺纤维化。尽管50多年前就开始努力寻找合适的辐射对策，但食品和药物管理局（FDA）尚未批准安全有效的辐射对策。因此，迫切需要辐射对策。肝细胞生长因子（HGF）是一种由间充质细胞产生的旁分泌生长因子；HGF通路的激活具有肺保护和修复作用，HGF治疗通过其在上皮细胞和内皮细胞中表达的c-Met受体减轻肺损伤。HGF还可以防止肺损伤后的纤维化重塑。然而，HGF蛋白或基因治疗并不是一种可行的治疗方法，尤其是在大规模伤亡的情况下。BB3是我们一流的，生物可利用的小分子HGF模拟物。它已经完成了I期临床试验，目前正在进行肾脏和心脏适应症的II期安全性和有效性试验。我们的研究旨在通过在辐射性肺炎和肺纤维化模型中进行疗效研究来开发BB3作为有效的辐射损伤缓解剂。这些研究对于后续的SBIR II期研究至关重要，其最终目标是制定有效的医疗对策以用于临床。

DESCRIPTION (provided by applicant): Nuclear accidents and terrorism present a serious threat for causing mass-casualty scenarios. In radiation events, many people receive non-uniform whole-body or partial-body irradiation. The risk of exposure to ionizing radiation due to terrorist activities could result in acute injury as well as long-term adverse health effects in thousands of people. The lung is one of the more radiosensitive organs and inhaling large quantities of radionuclides produces a spectrum of severe functional and morphological changes, ranging from radiation pneumonitis and pulmonary fibrosis. Although efforts to find suitable radiation countermeasures were initiated more than 50 years ago, no safe and effective radiation countermeasure has been approved by the Food and Drug Administration (FDA). Thus, there is a pressing need for radiation countermeasures. Hepatocyte growth factor (HGF) is a paracrine growth factor produced by cells of mesenchymal origin; Activation of the HGF pathway is pulmonary protective and reparative and HGF therapy mitigates lung injury via its c-Met receptor expressed in epithelial and endothelial cells. HGF also protects against fibrotic remodeling following lung injury. HGF protein or gene therapy, however, is not a viable treatment approach especially in a mass casualty setting. BB3 is our first-in-class, bioavailable small molecule HGF mimetic. It has completed Phase I clinical trials and is currently in Phase II safety and efficacy trials for renal and cardiac indications. Our studies are designed to develop BB3 as an effective mitigator of radiation injury by performing the efficacy studies in radiation-induced pneumonitis and pulmonary fibrosis models. These studies are critical for subsequent SBIR phase II studies with the ultimate objective of developing an effective medical countermeasure to use in the clinic.