GENE THERAPY FOR TREATMENT OF HEMOPHILIA B

基因疗法有望成为在最基本的病理学层面上治疗获得性和遗传性疾病的独特进步。血友病B患者的凝血因子IX水平不足。这种蛋白质通常在肝脏中表达。目前向肝脏输送基因的方法效率不是很高，而且会导致短期表达。然而，血清蛋白质，如因子IX，可以在异位部位产生并分泌到血清中。一种新型的血管内注射质粒DNA表达载体的方法可以高效地转染骨骼肌。该项目将使用这一简单而创新的方法来开发一种治疗血友病B的基因治疗方案。在这一阶段的应用中，建议进行实验，以优化在血管内注射质粒DNA表达载体后在大鼠体内表达人凝血因子IX的实验。在第二阶段的研究中，这种基因治疗方案将在犬血友病B模型中进行测试。这些实验将产生人体试验应用所需的临床前数据。血管内给药方法还将在第三阶段用于基因治疗方案的内部开发，用于Mirus内的其他凝血因子异常、苯丙酮尿症、α1抗胰蛋白酶缺乏症、补体因子缺乏症和其他血液或代谢疾病，并获得其他公司在其基因治疗应用中的许可。拟议的商业应用：根据这一提议开发的载体和方法学将使血友病B的基因治疗方案成为可能。

Gene therapy promises to be a singular advance in the treatment of both acquired and genetic diseases at the most fundamental levels of pathology. Hemophilia B patients express insufficient levels of factor IX. This protein is normally expressed in the liver. Current methods of gene delivery to the liver are not very efficient and results in short term expression. Yet, serum proteins such as factor IX can be produced at ectopic sites and secreted to the serum. A novel method of intravascular injection of plasmid DNA expression vectors results in highly efficient transfection of skeletal muscle. This project will use this simple and innovative approach to develop a gene therapy protocol for the treatment of hemophilia B. In this Phase I application, experiments are proposed to optimize expression of human factor IX in rats following intravascular delivery of plasmid DNA expression vectors. During the Phase II studies, this gene therapy protocol will be tested in a canine hemophilia B model. These experiments will generate the pre-clinical data required for a human trial application. The intravascular delivery methodology also will be used in Phase III for the internal development of gene therapy protocols for applications such as other clotting factor abnormalities, phenylketonuria, alpha1-antitrypsin deficiency, complement factor deficiencies, and other hematologic or metabolic disorders within Mirus and licensed to other companies for use within their gene therapy applications. PROPOSED COMMERCIAL APPLICATIONS: Vectors and methodology developed under this proposal should enable a gene therapy protocol for hemophilia B.