Muscle and Heart Function Restoration in a Limb Girdle Muscular Dystrophy 2I (LGMD2I) Mouse Model by Systemic FKRP Gene Delivery
Muscle and Heart Function Restoration in a Limb Girdle Muscular Dystrophy 2I (LGMD2I) Mouse Model by Systemic FKRP Gene Delivery
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DOI：
10.1038/mt.2014.141
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发表时间：
2014-11-01
影响因子：
12.4
通讯作者：
Xiao, Xiao
中科院分区：
文献类型：
--
作者：
Qiao, Chunping;Wang, Chi-Hsien;Xiao, Xiao
fukutin-related protein（FKRP）基因突变可导致多种疾病表型，包括轻度肢带型肌营养不良症21（LGMD 2 I）、重度Walker-Warburg综合征和肌-眼-脑疾病。FKRP缺乏导致肌肉和心脏中的α-肌营养不良聚糖（α-DG）低糖基化，这是肌营养不良聚糖病的生化标志。为了研究基因替代疗法，我们产生并表征了一种新的LGMD 2 I小鼠模型，其在小鼠等位基因中具有人类亮氨酸276突变为异亮氨酸（L276 I）。纯合基因敲入小鼠（L276 I（KI））在骨骼肌和心肌中模拟LGMD 2 I的经典晚发型表型。在新生儿年龄或9月龄的L276 I（KI）小鼠中通过AAV 9载体全身递送人FKRP基因，使得全身FKRP表达并恢复骨骼肌和心肌中的α-DG的糖基化。FKRP基因治疗改善了营养不良性病理和心肌病，如肌肉变性、纤维化和肌纤维膜渗漏，导致肌肉和心脏收缩功能的恢复。因此，这些结果证明基于FKRP基因置换的治疗是有效的。
Mutations in fukutin-related protein (FKRP) gene cause a wide spectrum of disease phenotypes including the mild limb-girdle muscular dystrophy 21 (LGMD2I), the severe Walker-Warburg syndrome, and muscle-eye-brain disease. FKRP deficiency results in a-dystroglycan (alpha-DG) hypoglycosylation in the muscle and heart, which is a biochemical hallmark of dystroglycanopathies. To study gene replacement therapy, we generated and characterized a new mouse model of LGMD2I harboring the human mutation leucine 276 to isoleucine (L276I) in the mouse alleles. The homozygous knock-in mice (L276I(KI)) mimic the classic late onset phenotype of LGMD2I in both skeletal and cardiac muscles. Systemic delivery of human FKRP gene by AAV9 vector in the L276I(KI) mice, at either neonatal age or at the age of 9 months, rendered body wide FKRP expression and restored glycosylation of alpha-DG in both skeletal and cardiac muscles. FKRP gene therapy ameliorated dystrophic pathology and cardiomyopathy such as muscle degeneration, fibrosis, and myofiber membrane leakage, resulting in restoration of muscle and heart contractile functions. Thus, these results demonstrated that the treatment based on FKRP gene replacement was effective.