High Expression Recombinant Factor VIII

描述(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，第一次在血友病患者中使用输血来止血，1968年，第一种商品化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年开始商业化。这被认为是一项显著的治疗改进，因为重组产品相对于血浆衍生产品具有公认的安全优势，后者被证明是导致1980年代S期间成千上万的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FVIII的发展以来，治疗甲型血友病的进展已经放缓。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)产生体液抗FVIII免疫反应，从而阻碍治疗效果，以及4)关节疾病的发病率。最先进的治疗方法每周多次输注FVIII产品。然而，许多患者只有在出血发作开始后才接受治疗，这些患者通常会因为目标关节(如膝盖)反复出血而患上关节病。除非全球FVIII供应增加，价格大幅下降，否则血友病A仍将是人类社会的重要健康负担。因此，寻求改进的治疗方法是有必要的。改善血友病的一种策略是开发改进的重组蛋白产品，例如更高效地制造或具有更高的止血效果。表达治疗公司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中的序列元素的识别，这些序列元素可以被修改以增加其生物合成。本研究的目的是提供可行性数据，以支持这样的概念，即高表达的FVIII替代产品可以比传统的人类重组FVIII产品更有效地制造出来。这些数据将支持一种新的FVIII替代产品的开发，该产品将改善血友病A的治疗。公共卫生相关性：血友病A是一种由于凝血因子VIII(FVIII)不足而引起的出血性疾病。目前对血友病的治疗依赖于输注血浆衍生或重组的FVIII产品来恢复循环中的FVIII活性。目前，由于产品成本的原因，治疗提供给血友病A患者的患者不到三分之一。除非全球FVIII供应增加，价格大幅下降，否则血友病A仍将是人类社会的一个重要健康负担，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 limitations of current treatment are 1) access to fVIII-replacement products, 2) the cost of fVIII- replacement products, 3) the development of humoral anti-fVIII immune responses that block treatment efficacy and 4) morbidity due to joint disease. State of the art treatment multiple infusions per week of fVIII product. However, many patients are treated only after the initiation of a bleeding episode and these patients typically develop joint arthropathy due to repeated bleeding into a target joint, e.g. knee. 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 feasibility data supporting the concept that a high-expression fVIII-replacement product can be manufactured more efficiently than traditional human recombinant fVIII products. These data will support the development 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, designated 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 with hemophilia A patients due to 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.