Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah 84112-5820, USA.
Mol Ther. 2012 Jul;20(7):1360-6. doi: 10.1038/mt.2012.62. Epub 2012 Apr 3.
Erythropoiesis-stimulating agents are widely used to treat anemia for chronic kidney disease (CKD) and cancer, however, several clinical limitations impede their effectiveness. Nonviral gene therapy systems are a novel solution to these problems as they provide stable and low immunogenic protein expression levels. Here, we show the application of an arginine-grafted bioreducible poly(disulfide amine) (ABP) polymer gene delivery system as a platform for in vivo transfer of human erythropoietin plasmid DNA (phEPO) to produce long-term, therapeutic erythropoiesis. A single systemic injection of phEPO/ABP polyplex led to higher hematocrit levels over a 60-day period accompanied with reticulocytosis and high hEPO protein expression. In addition, we found that the distinct temporal and spatial distribution of phEPO/ABP polyplexes contributed to increased erythropoietic effects compared to those of traditional EPO therapies. Overall, our study suggests that ABP polymer-based gene therapy provides a promising clinical strategy to reach effective therapeutic levels of hEPO gene.
促红细胞生成素刺激剂被广泛用于治疗慢性肾病（CKD）和癌症引起的贫血，但它们的有效性受到多种临床限制。非病毒基因治疗系统是解决这些问题的一种新方法，因为它们可以提供稳定和低免疫原性的蛋白质表达水平。在这里，我们展示了一种精氨酸接枝的生物还原型聚（二硫代氨基甲酸盐）（ABP）聚合物基因传递系统在体内转染人促红细胞生成素质粒 DNA（phEPO）以产生长期治疗性红细胞生成中的应用。单次系统注射 phEPO/ABP 超分子聚合物导致在 60 天内更高的红细胞压积水平，伴随着网织红细胞增多和高 hEPO 蛋白表达。此外，我们发现与传统 EPO 治疗相比，phEPO/ABP 超分子聚合物的独特时空分布有助于增加红细胞生成作用。总的来说，我们的研究表明，ABP 聚合物基基因治疗为达到有效治疗水平的 hEPO 基因提供了一种有前途的临床策略。
