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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1
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Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1

机译：通过将siRNA靶向整合素淋巴细胞功能相关抗原1，激活白细胞中的选择性基因沉默

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摘要

Silencing gene expression by RNAi is a powerful method for exploring gene function and validating drug targets and potentially for therapy. Lymphocytes and other primary blood cells are resistant to lipid-based transfection in vitro and are difficult to target in vivo. We show here that antibody-protamine fusion proteins targeting the human integrin lymphocyte function-associated antigen-1 (LFA-1) efficiently deliver siRNAs and specifically induce silencing in primary lymphocytes, monocytes, and dendritic cells. Moreover, a fusion protein constructed from an antibody that preferentially recognizes activation-dependent conformational changes in LFA-1 selectively targets activated leukocytes and can be used to suppress gene expression and cell proliferation only in activated lymphocytes. The siRNA-fusion protein complexes do not cause lymphocyte activation or induce IFN responses. K562 cells expressing latent WT or constitutively activated LFA-1 engrafted in the lungs of SCID mice are selectively targeted by intravenously injected fusion protein-siRNA complexes, demonstrating the potential in vivo applicability of LFA-1-directed siRNA delivery.
机译：RNAi使基因表达沉默是探索基因功能，验证药物靶标以及潜在治疗方法的强大方法。淋巴细胞和其他原代细胞在体外对基于脂质的转染具有抗性，并且难以在体内靶向。我们在这里显示针对人整联蛋白淋巴细胞功能相关抗原1（LFA-1）的抗体鱼精蛋白融合蛋白有效地传递siRNA，并特异性诱导原代淋巴细胞，单核细胞和树突状细胞沉默。此外，由抗体构建的融合蛋白可优先识别LFA-1的激活依赖性构象变化，并选择性地靶向激活的白细胞，可用于仅在激活的淋巴细胞中抑制基因表达和细胞增殖。 siRNA融合蛋白复合物不会引起淋巴细胞激活或诱导IFN反应。通过静脉内注射融合蛋白-siRNA复合物选择性靶向植入SCID小鼠肺部的表达潜伏WT或组成型激活的LFA-1的K562细胞，证明了LFA-1定向siRNA递送的潜在体内适用性。

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