Yanay Ofer, Barry Simon C, Flint Lisa Y, Brzezinski Margaret, Barton Randall W, Osborne William R A
Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
Hum Gene Ther. 2003 Nov 20;14(17):1587-93. doi: 10.1089/104303403322542239.
Recombinant erythropoietin (EPO) is widely administered for long-term treatment of anemia associated with renal failure and other chronic diseases. The ability to deliver EPO by gene therapy would have clinical and economic benefit. We compared autologous and allogeneic transduced primary vascular smooth muscle cells for their ability to provide sustained EPO gene expression when encapsulated in TheraCyte devices implanted subcutaneously (SQ) or intraperitoneally (IP) in rats. Cells were transduced with retrovirus vector LrEpSN encoding rat EPO cDNA. Rats that received either autologous or allogeneic transduced cells showed elevated hematocrits (HCTs) ranging from 50 to 79% that were sustained for more than 12 months. The HCT of control rats remained at baseline (45.8%). Rats that received second SQ implants of either autologous or allogeneic cells showed elevations in hematocrit that were sustained for up to 12 months, suggesting the absence of immunological responses to transduced cells or implant material. All experimental groups had statistically significant elevated HCT (p < 0.001) when compared with controls. Both SQ and IP implantation were equally effective in delivering EPO long term. There were no significant differences in white blood cell (WBC) or platelet (PLT) values between treated and control animals. Implantation of TheraCyte devices was well tolerated and histological evaluation of the devices up to 12 months after surgery revealed a high degree of vascularization and no evidence of host immune response. TheraCyte devices offer a simple and safe gene delivery system that provides sustained therapeutic gene expression, permit removal and implantation of new devices, and do not require immunosuppression of the host.
重组促红细胞生成素（EPO）被广泛用于长期治疗与肾衰竭及其他慢性疾病相关的贫血。通过基因疗法递送EPO将具有临床和经济效益。我们比较了自体和异体转导的原代血管平滑肌细胞，当它们被封装在植入大鼠皮下（SQ）或腹腔内（IP）的TheraCyte装置中时，其提供持续EPO基因表达的能力。用编码大鼠EPO cDNA的逆转录病毒载体LrEpSN转导细胞。接受自体或异体转导细胞的大鼠的血细胞比容（HCT）升高，范围为50%至79%，并持续超过12个月。对照大鼠的HCT保持在基线水平（45.8%）。接受自体或异体细胞第二次SQ植入的大鼠的血细胞比容升高，持续长达12个月，这表明对转导细胞或植入材料没有免疫反应。与对照组相比，所有实验组的HCT均有统计学意义的升高（p < 0.001）。SQ和IP植入在长期递送EPO方面同样有效。治疗组和对照组动物之间的白细胞（WBC）或血小板（PLT）值没有显著差异。TheraCyte装置的植入耐受性良好，术后长达12个月对装置的组织学评估显示血管化程度高，没有宿主免疫反应的证据。TheraCyte装置提供了一种简单安全的基因递送系统，可提供持续的治疗性基因表达，允许移除和植入新装置，并且不需要对宿主进行免疫抑制。
