Age-Dependent Echocardiographic and Pathologic Findings in a Rat Model with Duchenne Muscular Dystrophy Generated by CRISPR/Cas9 Genome Editing
Age-Dependent Echocardiographic and Pathologic Findings in a Rat Model with Duchenne Muscular Dystrophy Generated by CRISPR/Cas9 Genome Editing
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DOI：
10.1536/ihj.20-372
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发表时间：
2020-11-01
影响因子：
1.5
通讯作者：
Komuro, Issei
中科院分区：
文献类型：
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作者：
Sugihara, Hidetoshi;Kimura, Koichi;Komuro, Issei
杜氏肌营养不良症（DMD）是由肌营养不良蛋白基因突变引起的x连锁隐性肌病。虽然常规治疗改善了他们的预后，但不可避免的进行性心肌病仍然是DMD患者死亡的主要原因。为了探索新的治疗方案，需要一种合适的心脏受累动物模型。我们使用CRISPR/Cas9基因组编辑技术（DMD大鼠）生成了一个具有肌营养不良蛋白基因框外突变的大鼠模型。本研究的目的是评估他们的心脏功能和病理，为未来的实验提供基线数据，以制定DMD的治疗方案。与同龄野生大鼠相比，6月龄DMD大鼠超声心动图评价无显著差异。然而，10月龄DMD大鼠在左室（LV）分数缩短（P = 0.024）、左室侧壁组织多普勒峰值收缩速度（Sa） （P = 0.041）和右室（RV）自由壁（P = 0.004）方面均表现出明显的恶化。这些功能发现与组织学分析的纤维化分布一致。尽管心脏表型比预期的温和，但DMD大鼠的心脏受累分布和进展与DMD患者相似。这种动物可能是一种有用的模型，用于开发有效的药物和了解DMD患者进行性心力衰竭的潜在机制。
Duchenne muscular dystrophy (DMD) is X-linked recessive myopathy caused by mutations in the dystrophin gene. Although conventional treatments have improved their prognosis, inevitable progressive cardiomyopathy is still the leading cause of death in patients with DMD. To explore novel therapeutic options, a suitable animal model with heart involvement has been warranted. We have generated a rat model with an out-of-frame mutation in the dystrophin gene using CRISPR/Cas9 genome editing (DMD rats). The aim of this study was to evaluate their cardiac functions and pathologies to provide baseline data for future experiments developing treatment options for DMD. In comparison with age-matched wild rats, 6-month-old DMD rats showed no significant differences by echocardiographic evaluations. However, 10-month-old DMD rats showed significant deterioration in left ventricular (LV) fractional shortening (P = 0.024), and in tissue Doppler peak systolic velocity (Sa) at the LV lateral wall (P = 0.041) as well as at the right ventricular (RV) free-wall (P = 0.004). These functional findings were consistent with the fibrotic distributions by histological analysis. Although the cardiac phenotype was milder than anticipated, DMD rats showed similar distributions and progression of heart involvement to those of patients with DMD. This animal may be a useful model with which to develop effective drugs and to understand the underlying mechanisms of progressive heart failure in patients with DMD.