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Gene therapy for progressive kidney diseases using siRNA

使用 siRNA 治疗进行性肾病的基因疗法

基本信息

批准号：
17590827
负责人：
ISAKA Yoshitaka
金额：
$ 2.24万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590827/
关键词：
siRNA glomerulonephritis eri-1 TGF-beta エレクトロポレーション遺伝子導入 ERI-1 糸球体腎炎

项目摘要

Background ; We previous demonstrated that transfection of synthetic short interfering RNAs (siRNAs) targeting against TGF-β1 could be effective and therapeutic in silencing TGF-β1 expression in glomerulus, thereby ameliorated the progression of matrix expansion in anti-Thy-1 model of glomerulonephritis. However, a major concern in applying RNAi to gene therapy is the prolonged existence of silencing potential in vivo. Method ; We examined the duration of siRNA stability in kidney and muscle, and checked the tissue distribution of siRNase, eri-1. Thereafter, we tested the effect of siSTABLE^<TM> on progressive glomerulosclerosis model. Results ; A single introduction of siRNA for EGFP (siEGFP) or its expression vector into kidney resulted in the reduction of masangial EGFP expression only for up to two weeks, while transfection of siEGFP into the pretibial muscle silenced EGFP expression unexpectedly for more than 90 days. These observations could be explained by the different expression of eri-1 between kidney and muscle. In addition, transfection of ERI-1 resistant siSTABLE^<TM> for TGF-β significantly reducedglomerular matrix deposition in progressive glomerulosclerosis model. Conclusion ; Treatment with siRNA resistant to eri-1 may be effective and promising strategy for progressive renal disease.

背景;我们先前证明，针对TGF-β 1的合成短干扰RNA（siRNA）的转染可以有效和治疗性地沉默TGF-β 1在肾小球中的表达，从而改善抗Thy-1肾小球肾炎模型中基质扩张的进展。然而，将RNAi应用于基因治疗的一个主要问题是体内沉默潜力的长期存在。方法：我们检测了siRNA在肾脏和肌肉中的稳定时间，并检查了siRNase，eri-1的组织分布。此后，我们测试了siSTABLE ^对进行性肾小球硬化模型的作用。<TM>结果;一个单一的引入siRNA的EGFP（siEGFP）或其表达载体到肾脏导致masangial EGFP表达的减少只有长达两周，而转染siEGFP到胫骨前肌肉沉默EGFP表达意外超过90天。这些观察结果可能是由于肾脏和肌肉中eri-1的表达不同。此外，在进行性肾小球硬化模型中，转染TGF-β的ERI-1抗性siSTABLE ^显著减少肾小球基质沉积。<TM>结论：抗eri-1的siRNA治疗可能是治疗进展性肾病的有效和有前途的策略。