Long-term improvement in mdx cardiomyopathy after therapy with peptide-conjugated morpholino oligomers
Long-term improvement in mdx cardiomyopathy after therapy with peptide-conjugated morpholino oligomers
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DOI：
10.1093/cvr/cvp335
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发表时间：
2010-02-01
影响因子：
10.8
通讯作者：
Willis, Monte S.
中科院分区：
文献类型：
--
作者：
Jearawiriyapaisarn, Natee;Moulton, Hong M.;Willis, Monte S.
杜氏肌营养不良症（DMD）中发现的心肌病是导致30%的患者因心力衰竭而死亡的原因，此外还导致了许多DMD发病率。绕过dmd引起的突变以增加全身肌营养不良蛋白的策略已被证明是有希望的，但增加心脏肌营养不良蛋白仍然具有挑战性。本研究的目的是确定治疗性恢复心肌肌营养不良蛋白是否能改善x连锁肌营养不良（mdx）肌营养不良蛋白缺失小鼠由于治疗后一段时间的截断突变而导致的显著心脏肥大和舒张功能障碍。方法和结果给由于截断突变（mdx）而缺乏肌营养不良蛋白的小鼠注射富含精氨酸、穿透细胞、肽偶联的磷酸二酯morpholino寡聚物（PPMO），该寡聚物提供剪接开关寡核苷酸介导的外显子跳跃治疗，在mdx小鼠发展为可检测的心肌病之前恢复肌营养不良蛋白。PPMO成功地恢复了心肌肌营养不良蛋白的表达，保持了心肌肌膜的完整性，并阻止了mdx缺失小鼠随着时间的推移而发生的心脏病理的发展。通过超声心动图和二尖瓣的多普勒分析，我们发现PPMO治疗mdx小鼠可以在治疗开始后短短5-6周内预防假药治疗、年龄匹配的mdx小鼠中发现的心脏肥大和舒张功能障碍，这是DMD患者在疾病过程早期的特征。令人惊讶的是，尽管短期内心脏肌营养不良蛋白(
Aims The cardiomyopathy found in Duchenne muscular dystrophy (DMD) is responsible for death due to heart failure in similar to 30% of patients and additionally contributes to many DMD morbidities. Strategies to bypass DMD-causing mutations to allow an increase in body-wide dystrophin have proved promising, but increasing cardiac dystrophin continues to be challenging. The purpose of this study was to determine if therapeutic restoration of cardiac dystrophin improved the significant cardiac hypertrophy and diastolic dysfunction identified in X-linked muscular dystrophy (mdx) dystrophin-null mouse due to a truncation mutation over time after treatment.Methods and results Mice lacking dystrophin due to a truncation mutation (mdx) were given an arginine-rich, cell-penetrating, peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) that delivered a splice-switching oligonucleotide-mediated exon skipping therapy to restore dystrophin in mdx mice before the development of detectable cardiomyopathy. PPMO successfully restored cardiac dystrophin expression, preserved cardiac sarcolemma integrity, and prevented the development of cardiac pathology that develops in mdx-null mice over time. By echocardiography and Doppler analysis of the mitral valve, we identified that PPMO treatment of mdx mice prevented the cardiac hypertrophy and diastolic dysfunction identified in sham-treated, age-matched mdx mice, characteristic of DMD patients early in the disease process, in as little as 5-6 weeks after the initiation of treatment. Surprisingly, despite the short-term replacement of cardiac dystrophin (