Ex Vivo Gene Therapy of Hemophilia A

描述（由申请人提供）：血友病A是一种由因子VIII （fVIII）基因突变引起的出血性疾病，导致循环fVIII活性缺乏。目前的血友病治疗依赖于输注血浆源性或重组fVIII来恢复循环fVIII活性。这种形式的治疗1)昂贵，2)由于治疗的频率和静脉途径而难以维持，3)全世界仅向30%的A型血友病患者提供这种治疗。Expression Therapeutics的使命是开发产品，以改善a型血友病患者的标准治疗。我们的技术是基于fVIII中序列元素的鉴定，这些序列元素可以被修改以增加其生物合成。基因疗法有治愈a型血友病的潜力，然而在之前的3项临床试验中，所达到的循环fVIII活性水平低于治疗效果所需的水平，所有试验都在i期后结束。本申请中提出的研究目标是证明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。我们建议使用小鼠血友病a模型研究几种fVIII转基因构建物的体内表达。我们将研究利用含有高表达fVIII转基因基因的重组慢病毒载体对人干细胞/祖细胞进行基因修饰后的fVIII生物合成。证明fVIII高表达元件能够用于血友病A基因治疗的概念验证，将是表达治疗公司在血友病A改良治疗方法开发方面的一个重要里程碑。项目说明：血友病A是一种由凝血因子，即因子VIII （fVIII）的基因突变引起的出血性疾病。目前的血友病治疗依赖于输注血浆源性或重组fVIII来恢复循环fVIII活性。这种形式的治疗1)昂贵，2)由于治疗的频率和静脉途径而难以维持，3)全世界仅向30%的A型血友病患者提供这种治疗。因此，改进血友病A的治疗方法，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.