Lejnieks D V, Ramesh N, Lau S, Osborne W R
Department of Pediatrics, University of Washington, Seattle, WA, USA.
Blood. 1998 Aug 1;92(3):888-93.
To approach the goal of consistent long-term erythropoietin (Epo) expression in vivo, we developed an implantation procedure in which transduced autologous vascular smooth muscle was introduced into rats in a chamber created from a polytetrafluoroethylene (PTFE) ring placed under the serosa of the stomach. The implant became vascularized and permitted the long-term survival of smooth muscle cells expressing Epo. Hematocrits of treated animals increased rapidly and monitored over 12 months gave a mean value of 56.0 +/- 4. 0% (P < .001; n = 9), increased from a presurgery mean of 42.3 +/- 1. 6%. Hemoglobin levels rose from a presurgery mean of 15.2 +/- 0.4 g/dL and for 12 months were significantly elevated with a mean value of 19.5 +/- 1.3 g/dL (P < .001; n = 9). The hematocrit and hemoglobin levels of control animals receiving human adenosine deaminase (ADA)-expressing cells were not significantly different from baseline (P > .05; n = 5). In response to tissue oxygenation, kidney, and (to a lesser extent) liver are specific organs that synthesize Epo. Treated animals showed downregulation of endogenous Epo mRNA in kidney over a 12-month period. The PTFE implant provides sustained gene delivery, is safe, and is minimally invasive. It allows easy engraftment of transduced cells and may be applied generally to the systemic delivery of therapeutic proteins such as hormones and clotting factors.
为了实现体内长期稳定表达促红细胞生成素（Epo）的目标，我们开发了一种植入方法，即将转导的自体血管平滑肌引入大鼠体内，植入部位是由置于胃浆膜下的聚四氟乙烯（PTFE）环制成的腔室。植入物实现了血管化，使表达Epo的平滑肌细胞能够长期存活。接受治疗的动物的血细胞比容迅速升高，在12个月的监测期内，平均值为56.0±4.0%（P<0.001；n=9），术前平均值为42.3±1.6%。血红蛋白水平从术前平均值15.2±0.4 g/dL上升，在12个月内显著升高，平均值为19.5±1.3 g/dL（P<0.001；n=9）。接受表达人腺苷脱氨酶（ADA）细胞的对照动物的血细胞比容和血红蛋白水平与基线相比无显著差异（P>0.05；n=5）。作为对组织氧合的反应，肾脏以及（程度较轻的）肝脏是合成Epo的特定器官。接受治疗的动物在12个月内肾脏中内源性Epo mRNA出现下调。PTFE植入物可提供持续的基因递送，安全且微创。它便于转导细胞的植入，并且可普遍应用于治疗性蛋白质如激素和凝血因子的全身递送。
