Gene therapy for progressive renal diseases

毫无疑问，分子生物干预疗法已经成熟，它的潜力已经产生了巨大的兴奋。作为一种基因转移技术，HVJ-脂质体方法现已适用于肾脏疾病病理生理学的分子方面的分析，并进一步成为基因治疗的工具。我们证明，从转基因骨骼肌持续输送嵌合的可溶性转化生长因子-β受体也能抑制实验性肾小球肾炎细胞外基质的扩张。此外，我们还探讨了体内转导转化生长因子-β反义寡核苷酸到间质成纤维细胞是否能抑制单侧输尿管梗阻模型大鼠间质纤维化的进展。转化生长因子-β-1反义寡核苷酸可显著降低梗阻肾组织转化生长因子-β-1和I型胶原基因的表达，从而减轻输尿管梗阻后肾间质纤维化的程度。结合临床观察，转化生长因子-β的上调在各种肾脏纤维化的形成中起着重要作用，调控转化生长因子-β的过度表达可能为延缓肾脏疾病的进展提供一种新的治疗干预途径。

There is little doubt that molecular biological intervention therapy has come of age and tremendous excitements have emerged from its potential. A gene transfer technique, HVJ-liposome method is now applicable to the analysis of molecular aspects in pathophysiology of renal diseases, and further to a tool for gene therapy. We demonstrated that continuous delivery of chimeric soluble TGF-β receptor from the gene transferred skeletal muscle also inhibits the extracellular matrix expansion in experimental glomerulonephritis. Furthermore, we challenged whether in vivo gene transfer of antisense ODNs for TGF-β into interstitial fibroblasts can suppress the progression of interstitial fibrosis in unilateral ureteral obstruction model rats. Introduction of TGF-β1 antisense ODNs significantly reduced levels of TGF-β1 and types I collagen mRNA expression in obstructed kidneys, and consequently prevented the extent of interstitial fibrosis following ureteral obstruction. Taken together with clinical observation that up-regulation of TGF-β plays an important role in the formation of various kidney fibrosis, the manipulation of the overexpression of TGF-β may provide a novel way of therapeutic intervention to ameliorate the progression of the renal diseases.