Ye X, Rivera V M, Zoltick P, Cerasoli F, Schnell M A, Gao G, Hughes J V, Gilman M, Wilson J M
Institute for Human Gene Therapy, University of Pennsylvania, Philadelphia, PA 19104, USA.
Science. 1999 Jan 1;283(5398):88-91. doi: 10.1126/science.283.5398.88.
Stable delivery of a therapeutic protein under pharmacologic control was achieved through in vivo somatic gene transfer. This system was based on the expression of two chimeric, human-derived proteins that were reconstituted by rapamycin into a transcription factor complex. A mixture of two adeno-associated virus vectors, one expressing the transcription factor chimeras and one containing erythropoietin (Epo) under the control of a promoter responsive to the transcription factor, was injected into skeletal muscle of immune-competent mice. Administration of rapamycin resulted in 200-fold induction of plasma Epo. Stable engraftment of this humanized system in immune-competent mice was achieved for 6 months with similar results for at least 3 months in a rhesus monkey.
通过体内体细胞基因转移实现了治疗性蛋白质在药理控制下的稳定递送。该系统基于两种嵌合的、人源化蛋白质的表达，这两种蛋白质经雷帕霉素重组形成转录因子复合物。将两种腺相关病毒载体的混合物注射到免疫健全小鼠的骨骼肌中，一种载体表达转录因子嵌合体，另一种载体在对转录因子有反应的启动子控制下含有促红细胞生成素（Epo）。给予雷帕霉素导致血浆Epo诱导增加200倍。该人源化系统在免疫健全小鼠中稳定植入6个月，在恒河猴中至少3个月也得到了类似结果。
