Laminin α1 chain reduces muscular dystrophy in laminin α2 chain deficient mice
Laminin α1 chain reduces muscular dystrophy in laminin α2 chain deficient mice
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DOI：
10.1093/hmg/ddh190
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发表时间：
2004-08-15
影响因子：
3.5
通讯作者：
Durbeej, M
中科院分区：
文献类型：
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作者：
Gawlik, K;Miyagoe-Suzuki, Y;Durbeej, M
层粘连蛋白（LN）α 2链缺陷在人类和小鼠中导致严重形式的先天性肌营养不良症（CMD）。在这里，我们研究了小鼠中的LNalpha1链是否可以补偿LNalpha2链的缺失并防止肌营养不良症的发展。我们产生了在LNalpha2链缺陷小鼠的骨骼肌中表达LNalpha1链转基因的小鼠。LNalpha 1在肌肉中不正常表达，但转基因产生的LNalpha 1链被掺入肌肉基底膜，并使某些其他层粘连蛋白链（α 4，β 2）表达的补偿性变化正常化。在4个月大的小鼠中，LNalpha1链可以完全防止几种肌肉的肌营养不良症的发展，并部分防止其他肌肉的肌营养不良症的发展。LNalpha1链转基因不仅在很大程度上逆转了疾病的组织病理学特征，而且大大改善了小鼠的健康和寿命。通过LNalpha1链纠正LNalpha2链缺陷可作为CMD患者基因治疗的范例。
Laminin (LN) alpha2 chain deficiency in humans and mice leads to severe forms of congenital muscular dystrophy (CMD). Here, we investigated whether LNalpha1 chain in mice can compensate for the absence of LNalpha2 chain and prevent the development of muscular dystrophy. We generated mice expressing a LNalpha1 chain transgene in skeletal muscle of LNalpha2 chain deficient mice. LNalpha1 is not normally expressed in muscle, but the transgenically produced LNalpha1 chain was incorporated into muscle basement membranes, and normalized the compensatory changes of expression of certain other laminin chains (alpha4, beta2). In 4-month-old mice, LNalpha1 chain could fully prevent the development of muscular dystrophy in several muscles, and partially in others. The LNalpha1 chain transgene not only reversed the appearance of histopathological features of the disease to a remarkable degree, but also greatly improved health and longevity of the mice. Correction of LNalpha2 chain deficiency by LNalpha1 chain may serve as a paradigm for gene therapy of CMD in patients.