CLINICAL MODEL OF ERYTHROPOIETIN GENE THERAPY

描述(改编自《调查者摘要》)：长期目标 本研究的目的是为持续性骨质疏松症的基因治疗提供一种方法 促红细胞生成素治疗慢性阻塞性肺疾病贫血 肾功能衰竭。我们将评估一个合适的绵羊临床前模型 逆转录病毒转导的自体促红细胞生成素基因转移 种植在人造血管移植物中的血管平滑肌细胞。嫁接 将转化的促红细胞生成素分泌的平滑肌细胞接种到 以动静脉瘘的形式植入颈动脉和颈静脉 静脉给药治疗外科稳定性尿毒症绵羊贫血。 这项研究可能适用于患有慢性肾功能衰竭的患者 需要进行透析，需要植入假体。这样的移植物可以 预先植入基因改造的自体血管平滑肌以 输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8.5万例 肾功能衰竭的损失约为5亿美元。治疗这些疾病和其他疾病的能力 通过基因治疗，红细胞生成素反应性贫血的患者将 提供了重大的临床和经济效益。总体而言，这项研究将 为长期系统地交付提供一种广泛适用的方法 促红细胞生成素用于治疗对这种激素和其他激素敏感的贫血 治疗性蛋白质，如细胞因子和凝血因子。具体的 目的包括：构建新的三种基因载体，合成 重组EPO和酶联免疫吸附试验构建的最佳移植物的研制 应用于正常绵羊和动物的播种方法及其评价 手术造成稳定的尿毒症贫血。

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.