Restoration of human dystrophin following transplantation of exon-skipping-engineered DMD patient stem cells into dystrophic mice
Restoration of human dystrophin following transplantation of exon-skipping-engineered DMD patient stem cells into dystrophic mice
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DOI：
10.1016/j.stem.2007.09.016
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发表时间：
2007-12-01
期刊：
影响因子：
23.9
通讯作者：
Torrente, Yvan
中科院分区：
文献类型：
--
作者：
Benchaouir, Rachid;Meregalli, Mirella;Torrente, Yvan
Duchenne肌营养不良症(DMD)是一种遗传性疾病，由基因突变扰乱dystrophin mRNA阅读框架引起。在某些情况下，强制排除(跳过)单个外显子可以恢复阅读框架，产生较短但仍具有功能的蛋白质。在本研究中，我们构建了表达反义寡核苷酸的慢病毒载体，以诱导有效的外显子跳跃，并纠正CD133+干细胞DMD缺失引起的初始移码。从DMD患者的血液和肌肉中分离出来的表达成肌祖细胞的转基因CD133肌肉内和动脉内注射可显著恢复SCID/MDX小鼠的肌肉形态、功能和肌营养不良蛋白的表达。这些数据表明，自体移植血液或肌肉来源的CD133+细胞是治疗DMD的一种有前景的方法。此前，CD133+细胞经过基因改造，重新表达了功能性肌营养不良蛋白。
Duchenne muscular dystrophy (DMD) is a hereditary disease caused by mutations that disrupt the dystrophin mRNA reading frame. In some cases, forced exclusion (skipping) of a single exon can restore the reading frame, giving rise to a shorter, but still functional, protein. In this study, we constructed lentiviral vectors expressing antisense oligonucleotides in order to induce an efficient exon skipping and to correct the initial frameshift caused by the DMD deletion of CD133+ stem cells. The intramuscular and intra-arterial delivery of genetically corrected CD133 expressing myogenic progenitors isolated from the blood and muscle of DMD patients results in a significant recovery of muscle morphology, function, and dystrophin expression in scid/mdx mice. These data demonstrate that autologous engrafting of blood or muscle-derived CD133+ cells, previously genetically modified to reexpress a functional dystrophin, represents a promising approach for DMD.