GENE DELIVERY SYSTEMS FOR BRONCHIO-ALVEOLAR DISEASE

这项研究旨在开发非病毒基因药物来 治疗肺气肿、囊性纤维化、哮喘、 感染或COPD可能需要在下呼吸道表达基因 和肺泡腔。以前的研究已经证明，阳离子 DNA质粒的脂类制剂可有效摄取基因 直接滴注后进入上呼吸道上皮细胞。一个 直接滴注表达α1-抗胰蛋白酶的临床试验 (AAT)目前正在对AAT缺乏的患者进行。现在 工作的目的是开发吸入剂的配方，以提供 DNA质粒和基因表达的可重复性生物利用度 在下呼吸道和肺泡。Aat是一个领先的候选基因 用于肺基因治疗，并可能适用于各种急性或 慢性肺炎性疾病与遗传性 肺气肿(AAT缺乏症)。假设是以下表达式 在下呼吸道和肺泡内有足够水平的AAT将 保护肺部免受蛋白水解酶损伤。此第一阶段应用程序侧重于 关于开发适合临床使用的给药系统。第二阶段 将重点展示基因的药理作用 在疾病动物模型中的表达。

This research is directed at developing non-viral gene medicines to treat pulmonary diseases such as emphysema, cystic fibrosis, asthma, infections or COPD that may require gene expression in lower airways and alveolar spaces. Previous studies have demonstrated that cationic lipid formulations of DNA plasmids provide effective uptake of genes into epithelial cells of the upper airways after direct instillation. A clinical trial using direct instillation to express alpha 1- antitrypsin (AAT) in AAT deficient patients is currently underway. The present work is aimed at developing formulations for inhalation that provide reproducible bioavailability of the DNA plasmid and gene expression in the lower airways and alveolus. AAT is a leading candidate gene for pulmonary gene therapy and may be indicated for various acute or chronic pulmonary inflammatory disorders as well as for genetic emphysema (AAT deficiency). The hypothesis is that expression of AAT at sufficient levels within the lower airways and alveoli will protect the lung from protease injury. This Phase I application focuses on development of delivery systems suitable for clinical use. Phase II will focus on demonstrating the pharmacological effect of gene expression in animal models of disease.