High Expression Recombinant Factor VIII

高表达重组因子VIII

• 批准号: 7481687
• 负责人: Christopher Bradley Doering
• 金额: $ 10万
• 依托单位: EXPRESSION THERAPEUTICS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-15 至 2009-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7481687
• 关键词: Affect; Anabolism; Arts; Biochemical; Blood Clot; Blood Coagulation Factor; Blood Transfusion; Blood coagulation; Caring; Cell Culture System; Cells; Cessation of life; Child; Clinical; Cloning; Conditioned Culture Media; Data; Development; Disease; Drops; Elements; Endothelin-1; Factor VIII; Family suidae; Genes; Goals; HIV; Hamsters; Hemophilia A; Hemorrhage; Hemostatic Agents; Hepatitis C virus; Human; Hybrids; Immune response; In Vitro; Individual; Infection; Infusion procedures; Insecta; Ion-Exchange Chromatography Procedure; Joints; Kidney; Kinetics; Knee; Lead; Letters; Link; Longevity; M cell; Mammalian Cell; Medical; Mission; Modification; Morbidity - disease rate; Pathway interactions; Patients; Plasma; Plasma Proteins; Population; Post-Translational Protein Processing; Postoperative Period; Preparation; Price; Process; Production; Proteins; Protocols documentation; Public Health; Rate; Recombinant Proteins; Recombinants; Risk; Safety; Secretory Cell; Societies; Standards of Weights and Measures; System; Technology; Therapeutic; Thrombin; Time; Transgenes; Treatment Efficacy; Tyrosine; United States; Week; Yeasts; arthropathies; base; concept; cost; domain mapping; glycosylation; human F8 protein; immunogenicity; improved; intravenous administration; novel; recombinant antihemophilic factor VIII; sulfation

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.

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）产生阻碍治疗疗效的体液抗fVIII免疫应答，以及4）关节疾病导致的发病率。最先进的治疗方法，每周多次输注FVIII产品。然而，许多患者仅在出血事件开始后才接受治疗，这些患者通常由于目标关节（例如膝关节）反复出血而发生关节病。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，例如更有效地生产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。本研究的目的是提供可行性数据，支持高表达fVIII替代产品的生产效率高于传统人重组fVIII产品的概念。这些数据将支持开发一种新型fVIII替代产品，以改善血友病A的治疗。公共卫生相关性：血友病A是一种出血性疾病，由凝血因子（称为因子VIII（fVIII））不足引起。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，由于产品成本的原因，不到三分之一的血友病A患者接受了治疗。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。