Diverse lipid conjugates for functional extra-hepatic siRNA delivery in vivo
Diverse lipid conjugates for functional extra-hepatic siRNA delivery in vivo
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DOI：
10.1093/nar/gky1239
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发表时间：
2019-02-20
影响因子：
14.9
通讯作者：
Khvorova, Anastasia
中科院分区：
文献类型：
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作者：
Biscans, Annabelle;Coles, Andrew;Khvorova, Anastasia
基于小干扰RNA（siRNA）的疗法被证明是治疗肝脏相关疾病的有效方法。然而，肝外递送仍然具有挑战性，限制了siRNA的治疗效用。我们合成了一组十五个脂质缀合的siRNA，并系统地评估了缀合物对siRNA组织分布和功效的影响。通常，缀合物疏水性定义了清除程度和肝-肾分布特征。除了主要清除组织外，几种缀合物在肌肉、肺、心脏、肾上腺和脂肪中实现显著的siRNA积累。寡核苷酸分布到肝外组织与一些共轭物显着高于胆固醇，一个良好的研究共轭物，这表明改变共轭结构可以提高肝外输送。这些缀合的siRNA能够使肺、肌肉、脂肪、心脏和肾上腺中的功能性基因沉默。生产性沉默所需的水平每个组织不同（5-200 g/g），表明缀合物的化学性质影响组织依赖性细胞/细胞内运输机制。本文所述的缀合siRNA的收集使得能够在几种肝外组织中进行体内功能性基因调节，从而打开这些组织用于基因表达调节。本文报道的一组缀合siRNA的系统性评价以前没有研究过，表明脂质siRNA的化学工程对于推进RNA治疗领域至关重要。
Small interfering RNA (siRNA)-based therapies are proving to be efficient for treating liver-associated disorders. However, extra-hepatic delivery remains challenging, limiting therapeutic siRNA utility. We synthesized a panel of fifteen lipid-conjugated siRNAs and systematically evaluated the impact of conjugate on siRNA tissue distribution and efficacy. Generally, conjugate hydrophobicity defines the degree of clearance and the liver-to-kidney distribution profile. In addition to primary clearance tissues, several conjugates achieve significant siRNA accumulation in muscle, lung, heart, adrenal glands and fat. Oligonucleotide distribution to extra-hepatic tissues with some conjugates was significantly higher than with cholesterol, a well studied conjugate, suggesting that altering conjugate structure can enhance extra-hepatic delivery. These conjugated siRNAs enable functional gene silencing in lung, muscle, fat, heart and adrenal gland. Required levels for productive silencing vary (5-200 g/g) per tissue, suggesting that the chemical nature of conjugates impacts tissue-dependent cellular/intracellular trafficking mechanisms. The collection of conjugated siRNA described here enables functional gene modulation in vivo in several extra-hepatic tissues opening these tissues for gene expression modulation. A systemic evaluation of a panel of conjugated siRNA, as reported here, has not previously been investigated and shows that chemical engineering of lipid siRNAs is essential to advance the RNA therapeutic field.