A GENE BASED THERAPEUTIC FOR ACUTE LUNG INJURY

描述：(改编自申请者摘要)：成人呼吸系统 窘迫综合征(ARDS)是一种常见的临床综合征，其特征是急性 通常由败血症引起的肺损伤和呼吸衰竭。 死亡率仍然很高，需要新的治疗方法。首席调查员 提供了临床前证据表明α-1抗胰蛋白酶的表达 兔和仔猪肺内基因对内毒素所致肺损伤的保护作用 受伤。AAT基因是通过静脉注射的，使用一种特定的 导致AAT间隔化的质粒-阳离子脂质体制剂 转基因在肺内的表达。这是本申请的假设 将AAT基因输送到肺将保护未麻醉的仪器化 绵羊从内毒素引起肺血管收缩、肺水肿和 气体交换受损。利用仪表化未麻醉的绵羊模型， PI和合作调查员将：1)确定静脉注射的效果 注射质粒-阳离子脂质体制剂对全身血流动力学的影响 布洛芬预处理前后的肺力学和气体交换； 2)检测AAT基因对小鼠肺组织中AAT基因的影响 内毒素引起的肺血流动力学、肺血管改变 通透性、肺力学和气体交换；以及3)决定 内毒素诱导的肺损伤改变了有效地将 AAT基因通过静脉注射阳离子脂质体-质粒复合体， 并确定AAT基因是否传递到内毒素损伤的肺 加重先前存在的肺损伤。 建议的商业应用：不可用

DESCRIPTION: (Adapted from the Applicant's Abstract): Adult respiratory distress syndrome (ARDS) is a common clinical syndrome, characterized by acute lung injury and respiratory failure that commonly occurs as a result of sepsis. Mortality remains high and new therapies are needed. The Principal Investigator provides pre-clinical evidence that the expression of the alpha-1 antitrypsin gene in the lungs of rabbits and piglets protects from endotoxin induced lung injury. The AAT gene is delivered intravenously, using a specific plasmid-cationic liposome formulation that results in compartmentalized AAT transgene expression within the lung. It is the hypotheses of this application that AAT gene delivery to the lung will protect instrumented unanesthetized sheep from endotoxin induced pulmonary vasoconstriction, pulmonary edema and impaired gas exchange. Utilizing an instrumented unanesthetized sheep model, the PI and co-investigators will: 1) determine the effects of intravenous infusion of plasmid-cationic liposome formulations on systemic hemodynamics, lung mechanics and gas exchange with and without pretreatment with ibuprofen; 2) determine the effects of transfection of the lungs with the AAT gene on endotoxin induced alterations in pulmonary hemodynamics, lung vascular permeability, lung mechanics and gas exchange; and 3) determine whether endotoxin induced lung injury alters the ability to efficiently transfer the AAT gene by intravenous administration of cationic liposome-plasmid complexes, and to determine whether AAT gene delivery to endotoxin injured lungs potentiates preexisting lung injury. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE