A GENE-BASED THERAPEUTIC FOR PULMONARY HYPERTENSION

描述：（改编自研究者摘要）原发性肺部 高血压是中青年人常见的致死性疾病; 对发病机制了解甚少，也没有特异性治疗。的 目前使用的主要药物治疗是长期持续静脉注射 输注血管扩张剂前列腺素前列环素这种疗法 有效，但需要维持静脉导管和持续 静脉输注;唯一的选择是肺移植。的 不久前，研究人员发现， 与花生四烯酸环氧合酶（考克斯）基因，并实现选择性增加 在前列环素和PGE 2前列腺素类中， 肺动脉高压由第一阶段赠款支持的研究记录了 作为质粒-阳离子脂质体复合物的考克斯基因的气溶胶递送 在动物模型中可显著降低肺血管反应性， 其在解剖学和生理学上与人类相似， 对肺功能的影响研究人员假设， 在与阳离子脂质体复合的表达质粒中的考克斯基因将 防止生理和病理的发展和/或进展， 慢性肺动脉高压的变化。调查人员进一步推测， 这种疗法将被证明上级任何目前的治疗方法， 原发性肺动脉高压患者，并可能提供一个新的 用于治疗更大的患者群体的治疗方式， 继发性肺动脉高压在第二阶段申请中，PI将 确定：1）重复施用考克斯基因在 质粒-阳离子脂质体复合物气雾剂对肺功能的影响，2）前列腺素类 在未麻醉绵羊中的生成和肺血管反应性; 3） 确定是否通过气雾剂以一种或多种形式施用考克斯基因， 质粒-脂质体复合物将阻止持续性的 肺动脉高压与肺血管重构 慢性空气栓塞模型 高血压的绵羊;和4）提高效率的气雾剂输送 使用新一代气溶胶递送的质粒-阳离子脂质体复合物 装置和改进的脂质体-DNA制剂。 拟议商业应用：不可用

DESCRIPTION: (Adapted from the Investigator's abstract) Primary pulmonary hypertension is a uniformly fatal disease of young and middle aged people; there is little understanding of the pathogenesis and no specific therapy. The principal pharmacologic therapy in current use is chronic constant intravenous infusion of the vasodilator prostanoid, prostacyclin. This therapy is effective, but requires maintenance of an intravenous catheter and continuous intravenous infusion; the only alternative is lung transplantation. The investigators showed some time ago that it is possible to transfect the lungs with the arachidonate cyclooxygenase (COX) gene and achieve selective increases in prostacyclin and PGE2 prostanoids which are potentially therapeutic for pulmonary hypertension. Studies supported by this phase I grant have documented that aerosol delivery of the COX gene as a plasmid-cationic liposome complex can decrease pulmonary vascular reactivity significantly in an animal model which is anatomically and physiologically similar to humans with no adverse effects on lung function. The investigators hypothesize that aerosol delivery of the COX gene in an expression plasmid complexed with cationic liposomes will prevent development and/or progression of the physiologic and pathologic changes of chronic pulmonary hypertension. The investigators further speculate that this therapy will prove superior to any current therapy for the treatment of patients with primary pulmonary hypertension and may provide a new therapeutic modality for treatment of a much larger group of patients with secondary pulmonary hypertension. In this Phase II application, the PI will determine: 1) effects of repeated administration of the COX gene in a plasmid-cationic liposome complex by aerosol on lung function, 2) prostanoid generation and pulmonary vascular reactivity in unanesthetized sheep; 3) determine whether administration of the COX gene by aerosol in a plasmid-liposome complex will prevent development or progression of sustained pulmonary hypertension and pulmonary vascular remodeling in a well-characterized chronic air embolization model of sustained pulmonary hypertension in sheep; and 4) increase the efficiency of aerosol delivery of plasmid-cationic liposome complexes by using newer generation aerosol delivery devices and improved liposome-DNA formulations. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE