CLINICAL MODEL OF ERYTHROPOIETIN GENE THERAPY

描述（改编自研究者摘要）：长期目的 本研究的目的是为持续性的 促红细胞生成素的递送以治疗慢性贫血患者的贫血 肾衰竭 我们将评估一个适当的临床前绵羊模型， 使用逆转录病毒转导的自体红细胞生成素基因转移 将血管平滑肌细胞接种在人工血管移植物中。 移植物 接种转导的促红细胞生成素分泌平滑肌细胞， 作为动静脉瘘穿过颈动脉和颈静脉植入 静脉治疗手术诱导的稳定性尿毒症羊贫血。 这项研究可能适用于慢性肾功能衰竭患者， 且需要假体通路移植物。 这种移植物可以 用基因修饰的自体血管平滑肌来保存， 递送人促红细胞生成素。 在美国，估计每年的成本 重组促红细胞生成素治疗慢性贫血85,000例 肾衰竭的费用约为5亿美元。 治疗这些和其他疾病的能力 红细胞生成素反应性贫血患者，通过基因治疗， 提供重大的临床和经济效益。 总的来说，这项研究将 提供了一种广泛适用的方法，用于长期全身递送 促红细胞生成素治疗对这种激素有反应的贫血， 治疗性蛋白质如细胞因子和凝血因子。 具体 目的包括：构建新的三基因载体，合成 重组Epo，ELISA构建，优化移植物的开发 接种程序及其在正常绵羊和动物中的评价 手术造成稳定的尿毒症性贫血

DESCRIPTION (Adapted from Investigator's Abstract): The long-term objective of this research is to provide a gene therapy method for the sustained delivery of erythropoietin to treat the anemia of patients with chronic renal failure. We will evaluate an appropriate pre-clinical sheep model of erythropoietin gene transfer using retrovirally transduced autologous vascular smooth muscle cells seeded in a prosthetic vascular graft. Grafts seeded with transduced erythropoietin-secreting smooth muscle cells will be implanted as arteriovenous fistulae across the carotid artery and jugular vein to treat the anemia of sheep with surgically induced stable uremia. This research may be applied to patients with chronic renal failure who are subject to dialysis and require prosthetic access grafts. Such grafts can be preseeded with autologous vascular smooth muscle genetically modified to deliver human erythropoietin. In the USA the estimated annual cost of recombinant erythropoietin for the 85,000 patients with anemia of chronic renal failure is about $500 million. The ability to treat these, and other patients with erythropoietin-responsive anemias, by gene therapy would provide major clinical and economic benefits. Overall, this research will provide a broadly applicable method for the long-term systemic delivery of erythropoietin to treat anemias responsive to this hormone and also other therapeutic proteins such as cytokines and clotting factors. The specific aims include: the construction of novel three gene vectors, synthesis of recombinant Epo, and ELISA construction, the development of optimal graft seeding procedures and their evaluation in normal sheep and animals with surgically created stable uremic anemia.