High Expression Recombinant Factor VIII

描述（由申请人提供）：血友病（A和B）是一种罕见的出血性疾病，已投入了大量的科学和医学努力。1840年，输血首次用于血友病患者的术后止血，1968年，第一个商业化的凝血因子浓缩物问世。1984年fVIII基因的克隆促进了重组fVIII蛋白产品的开发，该产品于1992年上市。这被认为是一种显著的治疗改进，这是由于重组产品相对于血浆衍生产品具有明显的安全性优势，血浆衍生产品被证明是20世纪80年代期间数千名血友病患者感染人类免疫缺陷病毒和/或丙型肝炎病毒的原因。自重组凝血因子VIII开发以来，血友病A的治疗进展已经放缓。目前治疗的局限性是1）获得fVIII替代产品，2）fVIII替代产品的成本，3）抗fVIII免疫应答的发展阻碍了治疗疗效，4）关节疾病导致的发病率。除非全球FVIII供应增加且价格显著下降，否则血友病A仍将是人类社会的重要健康负担。因此，有必要寻求改进的治疗方法。改善血友病A护理的一种策略是开发改进的重组蛋白产品，例如更有效地制造或具有增加的止血功效。Expression Therapeutics的使命是开发能够改善血友病A患者治疗的产品。我们的技术是基于对FVIII内序列元件的鉴定，这些序列元件可以被修饰以增加其生物合成。目前研究的目的是提供获得FDA批准进行1期人体临床试验所需的临床前数据，该试验使用高表达fVIII替代产品，该产品比传统的人重组fVIII产品更有效。这些数据将支持一种新型fVIII替代产品的商业化，该产品将改善血友病A的治疗。 公共卫生相关性：血友病A是一种由凝血因子VIII（fVIII）不足引起的出血性疾病。目前血友病的治疗依赖于输注血浆衍生或重组fVIII产品以恢复循环fVIII活性。目前，由于产品成本过高，只有不到三分之一的患者接受治疗。除非全球FVIII供应增加且价格显著下降，否则血友病A仍将是人类社会的重要健康负担，因此，有必要寻求改进的治疗方法。

DESCRIPTION (provided by applicant): The hemophilias (A and B) are rare bleeding disorders toward which much scientific and medical effort has been devoted. In 1840, blood transfusion was used for the first time to stop post-operative bleeding in a hemophilia patient and in 1968 the first commercial coagulation factor concentrate became available. The cloning of the fVIII gene in 1984 facilitated the development of recombinant fVIII protein products that became commercially available in 1992. This was viewed as a dramatic therapeutic improvement due to the perceived safety advantage recombinant products have over plasma-derived products, which proved responsible for the infection of thousands of patients with hemophilia with human immunodeficiency virus and/or hepatitis C virus during the 1980's. Since the development of recombinant fVIII, progress in the treatment of hemophilia A has slowed. The current limitations to treatment are 1) access to fVIII-replacement products, 2) the cost of fVIII- replacement products, 3) the development of anti-fVIII immune responses that block treatment efficacy and 4) morbidity due to joint disease. Unless the worldwide fVIII supply increases and prices drop significantly, hemophilia A will remain an important heath burden to human society. Therefore, the search for improved therapeutics is warranted. One strategy for improving hemophilia A care is to develop improved recombinant- protein products, e.g. manufactured more efficiently or have increased hemostatic efficacy. The mission of Expression Therapeutics is to develop products that will improve the 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. The goal of the current study is to provide preclinical data necessary to get FDA approval to conduct a phase 1 human clinical trial using a high-expression fVIII-replacement product that can be manufactured more efficiently than traditional human recombinant fVIII products. These data will support the commercialization of a novel fVIII-replacement product that will improve the treatment of hemophilia A. PUBLIC HEALTH RELEVANCE: Hemophilia A is a bleeding disorder caused by the insufficiency of a blood clotting factor, termed factor VIII (fVIII). Current treatment for hemophilia relies on infusion of plasma-derived or recombinant fVIII products to restore circulating fVIII activity. Currently, treatment is offered to less than one-third of all patients due to excessive product cost. Unless the worldwide fVIII supply increases and prices drop significantly, hemophilia A will remain an important heath burden to human society, and therefore, the search for improved therapeutics is warranted.