cGMP Recombinant FIX for IV & Oral Hemophilia B Therapy

用于 IV 的 cGMP 重组 FIX

• 批准号: 6847346
• 负责人: William H Velander
• 金额: $ 200.21万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-06 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6847346
• 关键词: biotechnology; biotherapeutic agent; blood /lymphatic pharmacology; blood disorder chemotherapy; coagulation factor IX; disease /disorder model; dogs; drug design /synthesis /production; genetically modified animals; hemophilia B; hemostasis; human tissue; intravenous administration; laboratory mouse; nonhuman therapy evaluation; oral administration; protein purification; recombinant proteins; swine

DESCRIPTION (provided by applicant): Hemophilia B is a bleeding disorder resulting from congenital deficiency of coagulation protein Factor IX. Without optimal therapy, patients suffer crippling debilitations, chronic pain, and cognitive impairment. Optimal therapy - frequent dosing with Factor IX to reduce bleeding episode frequency - is currently available to only a small fraction of U.S. patients, largely because of cost and limited supply; 80% of the world's hemophilia patients receive no therapy. The long-term goal of this research is development of an abundant, pure, safe, and effective therapy for the global hemophilia patient population using recombinant human coagulation proteins produced in the milk of transgenic pigs. This proposal describes studies that are based upon innovative bioengineering technologies to refine and scale-up production of clinical grade Factor IX, characterize product formulated for intravenous dosage, complete animal studies required for clinical trials, and ultimately develop an oral dosage form to provide optimal therapy for U.S. hemophilia B patients. This approach capitalizes on existing genetically engineered transgenic pigs that synthesize up to 1000 IU/ml (4 g/L) of human Factor IX in milk and preliminary evidence for favorable hemostatic and pharmacokinetic properties of this purified Factor IX in a hemophilia B mouse model. A high probability of success is expected because of the soundness and state of development of the basic research already completed and the breadth and complementarity of the strengths of the team. Dr. J. Cooper of ProGenetics LLC will supply FDA- and USDA-compliant Factor IX milk. At the Univ. Nebraska-Lincoln, Dr. M. Meagher provides expertise in bioprocess engineering and current Good Manufacturing Practices production of recombinant proteins; Drs. W. Velander and K. Van Cott contribute expertise in transgenic animal engineering and characterization of human Factor IX. Dr. M. Manning of Colorado State University brings expertise in the formulation of stabilized liquid and lyophilized proteins for oral and injectable dosing. Dr. S. Abramson of LifeSci Partners has two decades of biopharmaceutical development experience encompassing clinical, technical, and regulatory expertise, including AlphaNine(r)SD (purified plasma-derived Factor IX). Drs. P. Monahan and T. Nichols of UNC-Chapel Hill have unique preclinical experience with hemophilia B mice and dogs that will be used to test the safety and efficacy of the Factor IX products.

描述（由申请方提供）：血友病B是一种由先天性凝血蛋白因子IX缺乏引起的出血性疾病。如果没有最佳的治疗，患者会遭受严重的衰弱、慢性疼痛和认知障碍。最佳治疗-频繁使用因子IX以减少出血发作频率-目前仅适用于一小部分美国患者，主要是由于成本和供应有限;世界上80%的血友病患者没有接受治疗。本研究的长期目标是使用转基因猪乳汁中产生的重组人凝血蛋白为全球血友病患者群体开发丰富、纯净、安全和有效的治疗方法。该提案描述了基于创新生物工程技术的研究，以改进和扩大临床级因子IX的生产，表征静脉给药制剂的产品，完成临床试验所需的动物研究，并最终开发口服剂型，为美国血友病B患者提供最佳治疗。该方法利用了现有的在乳汁中合成高达1000 IU/ml（4 g/L）人因子IX的基因工程转基因猪，以及该纯化因子IX在血友病B小鼠模型中有利的止血和药代动力学性质的初步证据。由于已经完成的基础研究的健全性和发展状况以及团队力量的广度和互补性，预计成功的可能性很高。ProGenetics LLC的J.库珀博士将提供符合FDA和USDA标准的因子IX牛奶。在内布拉斯加州林肯大学，M. Meagher提供生物工艺工程和重组蛋白生产的现行良好生产规范方面的专业知识; Velander和K.货车科特在转基因动物工程和人类因子IX的表征方面贡献了专业知识。M博士科罗拉多州立大学的曼宁带来了口服和注射给药的稳定液体和冻干蛋白质配方的专业知识。Dr. S. LifeSci Partners的Abramson拥有20年的生物制药开发经验，包括临床、技术和监管专业知识，包括AlphaNine（r）SD（纯化血浆衍生因子IX）。P. Monahan和T. Nichols of UNC-Chapel Hill在血友病B小鼠和犬方面拥有独特的临床前经验，这些经验将用于测试因子IX产品的安全性和有效性。