Polymeric gene delivery of ischemia-inducible VEGF significantly attenuates infarct size and apoptosis following myocardial infarct
Polymeric gene delivery of ischemia-inducible VEGF significantly attenuates infarct size and apoptosis following myocardial infarct
复制标题
DOI：
10.1038/gt.2008.146
复制
发表时间：
2009-01-01
期刊：
影响因子：
5.1
通讯作者：
Bull, D. A.
中科院分区：
文献类型：
--
作者：
Yockman, J. W.;Choi, D.;Bull, D. A.
临床上有益的心肌基因治疗的发展已被减缓依赖于使用病毒载体和非生理性，组成型基因表达。为了具体解决这些问题，我们已经开发了一种非病毒基因载体，水溶性脂质聚合物（WSLP），和缺血诱导的质粒构建表达血管内皮生长因子（VEGF），pRTP 801-VEGF，治疗心肌缺血和梗死。结扎兔的回旋支动脉，然后注射（a）WSLP载体中的缺血诱导型VEGF基因构建体;（B）WSLP载体中的组成型表达或未调节的SV-VEGF基因构建体;（c）单独的WSLP载体;或（d）不注射治疗。治疗4周后，单独结扎导致48 +/- 7%的左心室梗死。单独注射WSLP载体，49 +/-6%的左心室梗死（P = NS）。组成型表达的基因构建体SV-VEGF将梗死面积减少至左心室的32 ± 7%（P = 0.007）。缺血诱导基因构建体RTP 801-VEGF进一步将梗死面积减少至左心室的13 ± 4%（P < 0.001）。使用非病毒载体递送缺血诱导型VEGF构建体在治疗急性缺血性心肌中是有效的。
The development of clinically beneficial myocardial gene therapy has been slowed by reliance on the use of viral carriers and non-physiologic, constitutive gene expression. To specifically address these issues, we have developed a non-viral gene carrier, water-soluble lipopolymer (WSLP), and an ischemia-inducible plasmid construct expressing vascular endothelial growth factor (VEGF), pRTP801-VEGF, to treat myocardial ischemia and infarction. Rabbits underwent ligation of the circumflex artery followed by injection of (a) an ischemia-inducible VEGF gene construct in a WSLP carrier; (b) a constitutively expressed, or unregulated, SV-VEGF gene construct in a WSLP carrier; (c) WSLP carrier alone; or (d) no injection therapy. Following 4 weeks treatment, ligation alone resulted in infarction of 48 +/- 7% of the left ventricle. With injection of WSLP carrier alone, 49 +/- 6% of the left ventricle was infarcted (P = NS). The constitutively expressed gene construct, SV-VEGF, reduced the infarct size to 32 +/- 7% of the left ventricle (P = 0.007). The ischemia-inducible gene construct, RTP801-VEGF, further reduced the infarct size to 13 +/- 4% of the left ventricle (P < 0.001). The use of a non-viral carrier to deliver an ischemia-inducible VEGF construct is effective in the treatment of acutely ischemic myocardium.