Cell-penetrating peptide-conjugated antisense oligonucleotides restore systemic muscle and cardiac dystrophin expression and function
Cell-penetrating peptide-conjugated antisense oligonucleotides restore systemic muscle and cardiac dystrophin expression and function
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DOI：
10.1093/hmg/ddn293
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发表时间：
2008-12-15
影响因子：
3.5
通讯作者：
Wood, Matthew J. A.
中科院分区：
文献类型：
--
作者：
Yin, HaiFang;Moulton, Hong M.;Wood, Matthew J. A.
反义寡核苷酸 (AO) 有可能通过外显子跳跃来恢复大多数杜氏肌营养不良症 (DMD) 患者的框内转录本，从而诱导功能性肌营养不良蛋白表达。在肌营养不良症 (mdx) 小鼠模型中进行高剂量全身给药后，吗啉代氨基磷酸酯 (PMO) 和 2'-O-甲基硫代磷酸酯 RNA (2'Ome RNA) 化学物质的 AO 已被证明可以恢复骨骼肌中肌营养不良蛋白的表达，但不能恢复心脏中的肌营养不良蛋白表达。利用两种基本的富含精氨酸的细胞穿透肽的细胞转导特性，我们证明了通过单次低剂量注射肽缀合的 PMO AO，可以对成年营养不良 mdx 小鼠全身肌肉和心脏组织中的肌营养不良蛋白表达进行广泛的系统校正。这种方法足以恢复外周肌肉和心脏组织中均匀、高水平的肌营养不良蛋白表达，肌营养不良蛋白相关蛋白复合物的肌膜重新定位和肌肉功能的改善。因此，肽缀合的 AO 具有系统纠正 DMD 表型的巨大潜力。
Antisense oligonucleotides (AOs) have the potential to induce functional dystrophin protein expression via exon skipping by restoring in-frame transcripts in the majority of patients suffering from Duchenne muscular dystrophy (DMD). AOs of morpholino phosphoroamidate (PMO) and 2'-O-methyl phosphorothioate RNA (2'Ome RNA) chemistry have been shown to restore dystrophin expression in skeletal muscle but not in heart, following high-dose systemic delivery in murine models of muscular dystrophy (mdx). Exploiting the cell transduction properties of two basic arginine-rich cell penetrating peptides, we demonstrate widespread systemic correction of dystrophin expression in body-wide muscles and cardiac tissue in adult dystrophic mdx mice, with a single low-dose injection of peptide-conjugated PMO AO. This approach was sufficient to restore uniform, high-level dystrophin protein expression in peripheral muscle and cardiac tissue, with robust sarcolemmal relocalization of the dystrophin-associated protein complex and functional improvement in muscle. Peptide-conjugated AOs therefore have significant potential for systemic correction of the DMD phenotype.