Efficient Gene Silencing in Brain Tumors with Hydrophobically Modified siRNAs.
Efficient Gene Silencing in Brain Tumors with Hydrophobically Modified siRNAs.
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DOI：
10.1158/1535-7163.mct-17-1144
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发表时间：
2018-06
影响因子：
5.7
通讯作者：
Khvorova A
中科院分区：
文献类型：
--
作者：
Osborn MF;Coles AH;Golebiowski D;Echeverria D;Moazami MP;Watts JK;Sena-Esteves M;Khvorova A
胶质母细胞瘤（GBM）是原发性脑肿瘤中最常见和最致命的形式，中位和两年生存率分别为14.5个月和18%。新的治疗药物的缺乏源于高度适应性肿瘤的复杂生物学，它使用多种生存和增殖机制来绕过当前的治疗方法。在这里，我们研究了新一代小干扰rna （sirna）在胸腺裸鼠移植人胶质瘤干细胞样细胞（GSCs）产生的正位脑瘤中沉默基因表达的效力。我们证明胆固醇结合的核酸酶抗性sirna （cholo - hsirna）在GBM神经球中减少mRNA和沉默荧光素酶表达90%。此外，单次瘤内注射后，choll - hsirna在脑肿瘤中广泛分布，实现持续有效的肿瘤特异性基因沉默（>45% mRNA和>90%蛋白）。这个现成的平台是序列无关的，可以适应一个或多个候选GBM驱动基因，提供了一种直接的方法来调节体内GBM生物学。
Glioblastoma (GBM) is the most common and lethal form of primary brain tumor with dismal median and two-year survivals of 14.5 months and 18%, respectively. The paucity of new therapeutic agents stems from the complex biology of a highly adaptable tumor that uses multiple survival and proliferation mechanisms to circumvent current treatment approaches. Here, we investigated the potency of a new generation of small interfering RNAs (siRNAs) to silence gene expression in orthotopic brain tumors generated by transplantation of human glioma stem-like cells (GSCs) in athymic nude mice. We demonstrate that cholesterol-conjugated, nuclease-resistant siRNAs (Chol-hsiRNAs) decrease mRNA and silence luciferase expression by 90% in vitro in GBM neurospheres. Furthermore, Chol-hsiRNAs distribute broadly in brain tumors after a single intratumoral injection, achieving sustained and potent (>45% mRNA and >90% protein) tumor-specific gene silencing. This readily available platform is sequence-independent and can be adapted to target one or more candidate GBM driver genes, providing a straightforward means of modulating GBM biology in vivo.