多功能性支化聚（β-氨基酯）基因载体的构建及其在帕金森氏症疾病治疗中的应用

基因疗法具有巨大临床潜力，制约其应用的核心瓶颈之一是缺乏安全而有效的基因载体。最近本课题组利用二乙烯基酯类、三丙烯酸酯类单体与小分子有机氨类的A2+B3+C2类型迈克尔加成反应成功合成了新型支化聚（β-氨基酯）（HPAE），并初步研究了其基因递送行为，结果表明在多种细胞，HPAE的基因转染效率均显著高于Lipofectmaine2000等试剂。本项目拟在前期工作基础上进一步开发多功能性HPAE，通过优化聚合物的结构和组成来提升其性能，以克服基因递送过程中复合物穿透脂质体膜能力低，DNA释放难以控制及载体细胞毒性大等主要屏障，提高HPAE在组织细胞特别是神经以及星形胶质细胞中的基因转染效率和安全性，并以帕金森氏症疾病为模型进行评价。本项目拟阐明的多功能性HPAE的结构和组成与其基因转染行为的关系，对开发阳离子基因转染试剂具有重要借鉴意义；并且能够开发出临床急需的帕金森氏症疾病基因治疗载体。

Gene therapy holds great promise, however, one of the main hurdles that limits the translation of gene therapy from bench to beside is the lack of high performance non-viral gene delivery vectors. Previously, we have successfully synthesized a new type of branched poly(β-amino esters) (HPAE) by A2+B3+C2 type Michael addition of diacrylates and triacrylates with amines, which provides a new platform for the development of non-viral gene delivery vectors. Preliminary gene transfection results showed that HPAE can effectively transfect a broad range of cell types with much higher transfection efficiency in comparison with Lipofectamine 2000 etc. In this project, we aim on optimizing the composition and structure of the HPAE, modifying their functionality to conquer the core barriers of gene delivery including low cellular membrane penetrating ability of polyplexes, incontrollable DNA release, high cytotoxicity of vectors thus to further improve the transfection efficiency and safety in various cell types, especially in neural cells and astrocytes. Parkinson's disease mouse model will be used to evaluate the performance of HPAE in vivo. The understanding of the polymer structure/property and transfection efficiency/safety of the HPAE would enlighten the development of non-viral vectors, also will provide vectors for the treatment of Parkinson's disease.