Effective Dystrophin Restoration by a Novel Muscle-Homing Peptide-Morpholino Conjugate in Dystrophin-Deficient mdx Mice
Effective Dystrophin Restoration by a Novel Muscle-Homing Peptide-Morpholino Conjugate in Dystrophin-Deficient mdx Mice
复制标题
新型肌肉归巢肽-吗啡啉缀合物在肌营养不良蛋白缺陷 mdx 小鼠中有效恢复肌营养不良蛋白
DOI：
10.1038/mt.2014.63
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发表时间：
2014-07-01
影响因子：
12.4
通讯作者：
Yin, HaiFang
中科院分区：
文献类型：
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作者：
Gao, Xianjun;Zhao, Jingwen;Yin, HaiFang
反义寡核苷酸(AO)介导的剪接矫正治疗Duchenne肌营养不良症在最近的2b期临床试验中显示出巨大的前景，但需要高剂量和高成本，而靶向递送可以降低这两者。我们先前已经证明了通过将由肌肉特异性多肽和细胞穿透性多肽组成的嵌合肽连接到mdx小鼠的AOS上，靶向递送AOS的可行性。虽然在肌肉中观察到摄取增加，但大部分多肽-AO结合物在肝脏中被发现。为了寻找更有效的肌肉归巢多肽，我们在成肌细胞中进行了体外生物扫描，发现了一种新的12肽(M12)，与骨骼肌相比，它与肝脏具有更好的结合能力。在mdx小鼠全身骨骼肌中，当连接到磷酸二氢吗啉低聚物时，dystrophin的表达水平接近正常水平的25%，握力显著恢复，而
Antisense oligonucleotide (AO)-mediated splice correction therapy for Duchenne muscular dystrophy has shown huge promise from recent phase 2b clinical trials, however high doses and costs are required and targeted delivery can lower both of these. We have previously demonstrated the feasibility of targeted delivery of AOs by conjugating a chimeric peptide, consisting of a muscle-specific peptide and a cell-penetrating peptide, to AOs in mdx mice. Although increased uptake in muscle was observed, the majority of peptide-AO conjugate was found in the liver. To search for more effective muscle-homing peptides, we carried out in vitro biopanning in myoblasts and identified a novel 12-mer peptide (M12) showing preferential binding to skeletal muscle compared to the liver. When conjugated to phosphorodiamidate morpholino oligomers, similar to 25% of normal level of dystrophin expression was achieved in body-wide skeletal muscles in mdx mice with significant recovery in grip strength, whereas