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首页> 外文期刊>American Journal of Pathology: Official Publication of the American Association of Pathologists >Laminin-111 protein therapy reduces muscle pathology and improves viability of a mouse model of merosin-deficient congenital muscular dystrophy
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Laminin-111 protein therapy reduces muscle pathology and improves viability of a mouse model of merosin-deficient congenital muscular dystrophy

机译：层粘连蛋白-111蛋白疗法可减少肌肉病理学并改善黑素缺乏型先天性肌营养不良的小鼠模型的生存能力

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摘要

Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is a lethal muscle-wasting disease that is caused by mutations in the LAMA2 gene, resulting in the loss of laminin-α2 protein. MDC1A patients exhibit severe muscle weakness from birth, are confined to a wheelchair, require ventilator assistance, and have reduced life expectancy. There are currently no effective treatments or cures for MDC1A. Laminin-α2 is required for the formation of heterotrimeric laminin-211 (ie, α2, β1, and γ1) and laminin-221 (ie, α2, β2, and γ1), which are major constituents of skeletal muscle basal lamina. Laminin-111 (ie, α1, β1, and γ1) is the predominant laminin isoform in embryonic skeletal muscle and supports normal skeletal muscle development in laminin-α2deficient muscle but is absent from adult skeletal muscle. In this study, we determined whether treatment with Engelbreth-Holm-Swarmderived mouse laminin-111 protein could rescue MDC1A in the dy W-/- mouse model. We demonstrate that laminin-111 protein systemically delivered to the muscles of laminin-α2deficient mice prevents muscle pathology, improves muscle strength, and dramatically increases life expectancy. Laminin-111 also prevented apoptosis in laminin-α2deficient mouse muscle and primary human MDC1A myogenic cells, which indicates a conserved mechanism of action and cross-reactivity between species. Our results demonstrate that laminin-111 can serve as an effective protein substitution therapy for the treatment of muscular dystrophy in the dy W-/- mouse model and establish the potential for its use in the treatment of MDC1A.
机译：缺乏肌球蛋白的先天性肌营养不良症1A型（MDC1A）是一种致命的肌肉萎缩性疾病，由LAMA2基因的突变引起，导致层粘连蛋白α2蛋白的损失。 MDC1A患者从出生起就表现出严重的肌肉无力，被限制在轮椅上，需要呼吸机协助，并且预期寿命缩短。当前没有有效的治疗或治愈MDC1A的方法。层粘连蛋白-α2是形成异源三聚体层粘连蛋白-211（即α2，β1和γ1）和层粘连蛋白-221（即α2，β2和γ1）的必需元素，它们是骨骼肌基底层的主要成分。层粘连蛋白-111（即α1，β1和γ1）是胚胎骨骼肌中主要的层粘连蛋白同工型，支持层粘连蛋白-α2缺陷型肌肉中正常的骨骼肌发育，但成年骨骼肌中不存在。在这项研究中，我们确定了用Engelbreth-Holm-Swarmderived小鼠层粘连蛋白111蛋白治疗能否在dy W-/-小鼠模型中拯救MDC1A。我们证明了层粘连蛋白-111蛋白被系统地递送至层粘连蛋白-α2缺陷型小鼠的肌肉，可以防止肌肉病理，提高肌肉强度，并显着提高预期寿命。层粘连蛋白111还阻止了层粘连蛋白α2缺陷的小鼠肌肉和原代人MDC1A肌源性细胞的凋亡，这表明物种之间的作用和交叉反应性是保守的。我们的结果表明，层粘连蛋白111可以作为dy W-/-小鼠模型中肌营养不良症的有效蛋白质替代疗法，并为其在MDC1A的治疗中建立潜力。

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