Ex Vivo Gene Therapy of Hemophilia A

描述(由申请人提供)：血友病A是一种出血性疾病，由因子VIII(FVIII)基因突变引起，导致循环中FVIII活性不足。目前对血友病的治疗依赖于输注血浆衍生的或重组的FVIII来恢复循环中的FVIII活性。这种疗法1)昂贵，2)由于治疗的频率和静脉途径而难以维持，3)只提供给全世界30%的血友病A患者。表达治疗公司的使命是开发能够改善血友病A患者标准治疗的产品。我们的技术是基于对FVIII内序列元素的识别，这些序列元素可以被修改以增加其生物合成。基因治疗有可能治愈血友病A。然而，在之前的3项临床试验中，循环中FVIII的活性水平都低于治疗效果所需的水平，所有试验都在I期之后结束。本申请中提议的研究的目标是证明FVIII高表达元件在基于基因转移的血友病A治疗中的有效性。证明FVIII高表达元件能够用于血友病A的基因治疗的概念证明将是表达治疗公司在开发改进的血友病A治疗方法方面的一个重要里程碑。项目旁白血友病A是一种由一种凝血因子基因突变引起的出血性疾病，指定的凝血因子VIII(FVIII)。目前对血友病的治疗依赖于输注血浆衍生的或重组的FVIII来恢复循环中的FVIII活性。这种疗法1)昂贵，2)由于治疗的频率和静脉途径而难以维持，3)只提供给全世界30%的血友病A患者。因此，发展血友病A的改良治疗方法，如基因治疗，是必要的。

DESCRIPTION (provided by applicant): Hemophilia A is a bleeding disorder caused by mutations within the factor VIII (fVIII) gene that result in a deficiency of circulating fVIII activity. Current treatment for hemophilia relies on infusion of plasma-derived or recombinant fVIII to restore circulating fVIII activity. This form of therapy is 1) expensive, 2) hard to maintain due to the frequency and intravenous route of treatment, and 3) only offered to 30% of hemophilia A patients worldwide. The mission of Expression Therapeutics is to develop products that will improve the standard treatment of individuals with hemophilia A. Our technology is based on the identification of sequence elements within fVIII that can be modified to increase its biosynthesis. Gene therapy has the potential to cure hemophilia A. However in 3 previous clinical trials, the levels of circulating fVIII activity achieved were below that required for therapeutic efficacy and all trials ended following phase I. The goal of the studies proposed in this application is to demonstrate the effectiveness of fVIII high expression elements in a gene transfer-based treatment of hemophilia A. We propose to study the expression of several fVIII transgene constructs in vivo using the murine model of hemophilia A. Additionally, we will study fVIII biosynthesis from human stem/progenitor cells that are genetically modified using recombinant lentiviral vectors containing high expression fVIII transgenes. Demonstrating proof-of-concept that fVIII high expression elements are enabling to gene therapy of hemophilia A will represent a major milestone for Expression Therapeutics in the development of improved therapeutic treatments for hemophilia A. PROJECT NARATIVE Hemophilia A is a bleeding disorder caused by genetic mutation of a blood clotting factor, designated factor VIII (fVIII). Current treatment for hemophilia relies on infusion of plasma-derived or recombinant fVIII to restore circulating fVIII activity. This form of therapy is 1) expensive, 2) hard to maintain due to the frequency and intravenous route of treatment, and 3) only offered to 30% of hemophilia A patients worldwide. Therefore, the development of improved therapeutic treatments for hemophilia A, e.g. gene therapy, is warranted.