Vivo-Morpholinos: A non-peptide transporter delivers Morpholinos into a wide array of mouse tissues
Vivo-Morpholinos: A non-peptide transporter delivers Morpholinos into a wide array of mouse tissues
复制标题
DOI：
10.2144/000113005
复制
发表时间：
2008-12-01
期刊：
影响因子：
2.7
通讯作者：
Jiang, Shan
中科院分区：
文献类型：
--
作者：
Morcos, Paul A.;Li, Yongfu;Jiang, Shan
我们开发了一种新的转运蛋白结构，可以将吗啉代反义寡聚物有效递送到活体小鼠的多种组织中。该转运蛋白包含围绕三嗪核心组装的树突结构，该结构用于将八个胍头部基团定位在有效穿透细胞膜的构象中。该转运蛋白结构与 Morpholino 寡聚物缀合，形成称为 Vivo-Morpholino 的可递送产品。在 100% 血清存在的情况下，使用基于纠正前信使 RNA 中确定的剪接错误的严格阳性测试系统，Vivo-Morpholinos 被证明可以有效地进入培养细胞并在其中发挥作用。此外，在转基因小鼠的类似阳性测试系统中，Vivo-Molpholinos 被证明可以进入多种组织，所有评估组织中的目标剪接错误的校正都证明了这一点，包括小肠、结肠、胃、肝脏、肾脏和许多肌肉中近乎完全的剪接校正。最后，Vivo-Morpholinos 靶向 mdx 小鼠模型中包含提前终止密码子的外显子 23 的外显子跳跃，有效恢复肌营养不良蛋白的阅读框并恢复肌营养不良蛋白功能的表达。
We have developed a new transporter structure that provides effective delivery of Morpholino antisense oligomers into a wide variety of tissues in living mice. This transporter comprises a dendritic structure assembled around a triazine core which serves to position eight guanidinium head groups in a conformation effective to penetrate cell membranes. This transporter structure is conjugated to a Morpholino oligomer to form a delivery-enabled product referred to as a Vivo-Morpholino. Vivo-Morpholinos are shown to effectively enter and function within cultured cells in the presence of 100% serum using a rigorous positive test system based on correction of a defined splicing error in a pre-messenger RNA. In addition, Vivo-Molpholinos are demonstrated to enter into a wide variety of tissues in a similar positive test system in transgenic mice, as evidenced by correction of the targeted splicing error in all tissues assessed, including near-complete splice correction in the small intestine, colon, stomach, liver, kidney, and a number of muscles. Finally, Vivo-Morpholinos, which target the exon-skipping of exon 23 harboring a premature termination codon in the mdx mouse model, effectively restore the reading frame of dystrophin and restore expression of a functional of dystrophin protein.