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，已经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，第一个商用凝血因子浓缩物问世。1984年fVIII基因的克隆促进了重组fVIII蛋白产品的发展，该产品于1992年上市。这被认为是一个显著的治疗改进，因为重组产品比血浆衍生产品具有明显的安全性优势，血浆衍生产品在20世纪80年代被证明是导致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。自从重组fVIII开发以来，血友病A的治疗进展缓慢。目前治疗的限制是1)获得fVIII替代产品，2)fVIII替代产品的成本，3)抗fVIII免疫反应的发展阻碍了治疗效果，4)关节疾病引起的发病率。除非世界范围内的fVIII供应增加，价格大幅下降，否则A型血友病仍将是人类社会的一个重要健康负担。因此，寻找改进的治疗方法是必要的。改善A型血友病护理的一个策略是开发改进的重组蛋白产品，例如生产效率更高或止血效果更好。Expression Therapeutics的使命是开发能够改善a型血友病患者治疗的产品。我们的技术是基于fVIII中序列元素的识别，这些序列元素可以被修改以增加其生物合成。目前研究的目标是提供必要的临床前数据，以获得FDA批准进行1期人体临床试验，使用高表达的fVIII替代产品，可以比传统的人重组fVIII产品更有效地生产。这些数据将支持一种新的fviii替代产品的商业化，该产品将改善血友病a的治疗。

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.