Mazur W, Ali N M, Raizner A E, French B A
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030.
Tex Heart Inst J. 1994;21(1):104-11.
Restenosis continues to limit the efficacy of coronary angioplasty, despite the various mechanical and pharmaceutical interventions that have been employed. The migration, proliferation, and extracellular matrix production by vascular smooth muscle cells are processes integral to restenosis, and sustained local delivery of drugs at high concentration should curtail these vascular responses to balloon angioplasty. Our laboratory and others are exploring the potential of using somatic cell gene therapy to provide such treatment and thereby prevent restenosis. However, conventional methods of gene transfer fail to produce physiologic levels of recombinant protein in vivo. This obstacle might be overcome by using adenoviral vectors to mediate efficient direct gene transfer. Herein we summarize these developments and focus upon our laboratory's progress towards evaluating adenovirus-mediated gene therapy in porcine coronary arteries. Recombinant adenoviruses directing the expression of the beta-galactosidase and luciferase reporter genes were evaluated in cultured coronary vascular smooth muscle cells in vitro and in porcine coronary arteries in vivo. Following percutaneous transluminal gene transfer in vivo, recombinant adenoviruses were shown to produce 70- to 240-fold more reporter protein than that produced by Lipofectin-DNA complexes. Furthermore, the high levels of adenovirus-mediated gene expression were shown to persist for at least 14 days following catheterization. Additional histologic studies will be required to determine the cellular distribution of gene expression and to elucidate potential interactions between adenovirus and the host's immune system, but recombinant adenovirus appears to be a promising vector for evaluating gene therapy against coronary restenosis.
尽管已经采用了各种机械和药物干预措施，但再狭窄仍然限制了冠状动脉血管成形术的疗效。血管平滑肌细胞的迁移、增殖和细胞外基质产生是再狭窄所固有的过程，高浓度药物的持续局部递送应能抑制这些对球囊血管成形术的血管反应。我们实验室和其他机构正在探索使用体细胞基因治疗来提供这种治疗从而预防再狭窄的潜力。然而，传统的基因转移方法无法在体内产生生理水平的重组蛋白。使用腺病毒载体介导高效的直接基因转移可能会克服这一障碍。在此我们总结这些进展，并重点关注我们实验室在评估腺病毒介导的基因治疗在猪冠状动脉中的进展。在体外培养的冠状动脉血管平滑肌细胞和体内猪冠状动脉中评估了指导β-半乳糖苷酶和荧光素酶报告基因表达的重组腺病毒。在体内经皮腔内基因转移后，重组腺病毒产生的报告蛋白比脂质体-DNA复合物产生的多70至240倍。此外，腺病毒介导的高水平基因表达在插管后至少持续14天。还需要进行额外的组织学研究来确定基因表达的细胞分布，并阐明腺病毒与宿主免疫系统之间的潜在相互作用，但重组腺病毒似乎是评估针对冠状动脉再狭窄的基因治疗的一种有前景的载体。
