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 型和 B 型）是罕见的出血性疾病，人们对此投入了大量的科学和医学努力。 1840 年，首次使用输血来止血友病患者术后出血，并于 1968 年推出第一种商业凝血因子浓缩物。 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。由于重组产品相对于血浆衍生产品具有明显的安全优势，这被认为是一种巨大的治疗改进，血浆衍生产品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/或丙型肝炎的原因 20世纪80年代的病毒。自从重组 fVIII 开发出来以来，A 型血友病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) 体液抗 fVIII 免疫反应的发展阻碍治疗效果，4) 关节疾病引起的发病率。最先进的治疗每周多次输注 fVIII 产品。然而，许多患者仅在出血事件开始后才接受治疗，并且这些患者通常由于目标关节（例如关节）反复出血而发展为关节病。膝盖。除非全球 fVIII 供应量增加且价格大幅下降，否则 A 型血友病仍将是人类社会的重要健康负担。因此，有必要寻找改进的治疗方法。改善 A 型血友病护理的一项策略是开发改进的重组蛋白产品，例如制造更有效或具有更高的止血功效。 Expression Therapeutics 的使命是开发能够改善 A 型血友病患者治疗的产品。我们的技术基于对 fVIII 中序列元件的识别，可以对其进行修改以增加其生物合成。当前研究的目标是提供可行性数据，支持高表达 fVIII 替代产品可以比传统人类重组 fVIII 产品更有效地生产这一概念。这些数据将支持开发一种新型 fVIII 替代产品，该产品将改善 A 型血友病的治疗。 公共健康相关性：A 型血友病是一种由凝血因子（称为因子 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的或重组的 fVIII 产品来恢复循环 fVIII 活性。目前，由于产品成本的原因，只有不到三分之一的 A 型血友病患者能够接受治疗。除非全球 fVIII 供应增加且价格大幅下降，否则 A 型血友病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。