Gene therapy for treatment of hemophilia A

描述(由申请者提供)：基因疗法有望成为一种独特的疗法 获得性和遗传性疾病的最高治疗进展 病理学的基本层面。血友病A患者表达不足 因子VIII的水平。这种蛋白质主要在肝脏中表达。一个 血管内注射质粒DNA表达载体的新方法 结果高效地转导肝细胞。该项目将使用 这种简单而创新的基因转移方法开发了一种基因疗法 治疗血友病A的议定书，尽管有这样的承诺 非病毒基因治疗的方法，有两个问题需要解决 使其在临床上可行：1)目前的质粒DNA表达载体 不会导致长期表达；2)基因转移通常伴随着 肝细胞受损。 在这一阶段的应用中，提出了开发质粒DNA的实验 能够长期表达人第VIII因子的表达载体 (HF8)。我们将构建含有肝脏特异性启动子和hF8基因组的载体 序列。最近，一种类似的质粒DNA表达载体被描述为 表达人凝血因子IX超过6个月。第二阶段将重点放在 发展将裸露的pDNA送入肝脏的手术方法 在最小的肝脏毒性下，使用基于导管的技术 临床实践。这些实验将产生临床前数据 人体试验应用所需的。这些基因传递技术还可以 用于开发诸如以下应用的基因治疗方案 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病或新陈代谢 精神错乱。 建议的商业应用：不可用

DESCRIPTION (provided by applicant): 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 A patients express insufficient levels of factor VIII. This protein is primarily expressed in the liver. A novel method of intravascular injection of plasmid DNA expression vectors results in highly efficient transfection of hepatocytes. This project will use this simple and innovative gene transfer approach to develop a gene therapy protocol for the treatment of hemophilia A. Despite the promise of this non-viral gene therapy approach, there are two problems that have to be solved for it to be clinically-viable: 1) current plasmid DNA expression vectors do not result in long term expression; 2) gene transfer is often accompanied by hepatocyte damage. In this Phase I application, experiments are proposed to developed plasmid DNA expression vectors that will enable long-term expression of human factor VIII (hF8). We will generate vectors with liver specific promoters and hF8 genomic sequences. Recently, a similar plasmid DNA expression vector was described that expressed human factor IX for more than 6 months. Phase II will focus on developing the surgical approaches for delivering the naked pDNA to the liver with minimal liver toxicity, using catheter-based techniques frequently used in clinical practice. These experiments will generate the pre-clinical data required for a human trial application. These gene delivery techniques can also be used for the development of gene therapy protocols for applications such as other clotting factor abnormalities, phenylketonuria, alpha 1 -antitrypsin deficiency, complement factor deficiencies, and other hematologic or metabolic disorders. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE