aav递送shrna和人工mirna在体内敲除多药耐药转运体ABCC1和ABCC2

Journal of RNAi and gene silencing : an international journal of RNA and gene targeting research Pub Date : 2011-01-01 Epub Date: 2011-06-17

Florie Borel, Richard van Logtenstein, Annemart Koornneef, Piotr Maczuga, Tita Ritsema, Harald Petry, Sander Jh van Deventer, Peter Lm Jansen, Pavlina Konstantinova

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摘要

ABC转运蛋白输出临床相关药物，其过表达导致多药耐药。为了敲除ABC转运体ABCC1和ABCC2，共开发了13种shrna。使用血清型8的自互补腺相关病毒在体内测试了四个候选shRNA。在小鼠肝脏中观察到Abbc2强烈的特异性敲低，但代价是由于shRNA高表达导致RNAi机制过度饱和而导致毒性。随后的代人工mirna表现出更好的疗效。这些结果证明了通过aav向肝脏递送shrna敲除Abbc2的可行性，并鼓励在进一步的治疗开发中使用miRNA。

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In vivo knock-down of multidrug resistance transporters ABCC1 and ABCC2 by AAV-delivered shRNAs and by artificial miRNAs.

ABC transporters export clinically-relevant drugs and their over-expression causes multidrug resistance. In order to knock-down ABC transporters, ABCC1 and ABCC2, 13 shRNAs were developed. Four shRNA candidates were tested in vivo using self-complementary adeno-associated virus serotype 8. A strong, specific knock-down of Abbc2 was observed in mice liver, but at the cost of toxicity caused by oversaturation of the RNAi machinery due to high shRNA expression. Subsequent generation of artificial miRNAs showed better efficacy profile. These results demonstrate the feasibility of knocking down Abbc2 via AAV-delivered shRNAs to the liver, and encourage the use of miRNA in further therapeutics development.

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Journal of RNAi and gene silencing : an international journal of RNA and gene targeting research

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