GENE DELIVERY SYSTEMS FOR BRONCHIO-ALVEOLAR DISEASE

支气管肺泡疾病的基因递送系统

• 批准号: 2030988
• 负责人: KAREL PETRAK
• 金额: $ 10万
• 依托单位: VALENTIS, INC.
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-03-01 至 1997-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2030988
• 关键词: alpha 1 antitrypsin; cardiopulmonary disease; drug delivery systems; gene expression; gene targeting; gene therapy; immunocytochemistry; in situ hybridization; laboratory rabbit; laboratory rat; liposomes; pharmacokinetics; plasmids; reporter genes; respiratory disorder

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.

这项研究旨在开发非病毒基因药物 治疗肺部疾病，如肺气肿、囊性纤维化、哮喘、 可能需要下呼吸道基因表达的感染或慢性阻塞性肺病 和肺泡腔。 先前的研究表明，阳离子 DNA 质粒的脂质制剂可有效摄取基因 into epithelial cells of the upper airways after direct instillation. 一个 使用直接滴注表达α1-抗胰蛋白酶的临床试验 目前正在进行针对 AAT 缺陷患者的 AAT 治疗。 现在的 工作的目的是开发吸入制剂，以提供 DNA 质粒和基因表达的可重复生物利用度 在下呼吸道和肺泡。 AAT是主要候选基因 用于肺部基因治疗，可能适用于各种急性或 慢性肺部炎症性疾病以及遗传性疾病 肺气肿（AAT 缺乏）。 假设是表达式 下呼吸道和肺泡内 AAT 达到足够水平将 保护肺部免受蛋白酶损伤。 此一期申请重点 开发适合临床使用的输送系统。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。