Laminin-111 protein therapy after disease onset slows muscle disease in a mouse model of laminin-α2 related congenital muscular dystrophy
Laminin-111 protein therapy after disease onset slows muscle disease in a mouse model of laminin-α2 related congenital muscular dystrophy
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DOI：
10.1093/hmg/ddaa104
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发表时间：
2020-07-01
影响因子：
3.5
通讯作者：
Burkin, Dean J.
中科院分区：
文献类型：
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作者：
Barraza-Flores, Pamela;Bukovec, Katherine E.;Burkin, Dean J.
层粘连蛋白-α 2 相关先天性肌营养不良症 (LAMA2-CMD) 是一种由 LAMA2 基因突变引起的致命性肌肉疾病。层粘连蛋白-α2 对于肌肉基底层中层粘连蛋白-211 和-221 异源三聚体的形成至关重要。 LAMA2-CMD 患者从出生起就表现出肌张力低下和进行性肌肉丧失，导致发育迟缓、只能坐在轮椅上、呼吸功能不全和过早死亡。目前 LAMA2-CMD 尚无治愈或有效的治疗方法。多项研究表明 laminin-111 可以作为 LAMA2-CMD 的有效蛋白质替代疗法。研究表明，早期使用层粘连蛋白 111 蛋白进行治疗可延长预期寿命并改善肌肉病理和功能。由于 LAMA2-CMD 患者通常是在疾病晚期才被诊断出来的，因此尚不清楚在疾病晚期进行层粘连蛋白 111 蛋白治疗是否能产生有益的结果。在这项研究中，我们在 LAMA2-CMD 小鼠模型中测试了疾病发作后层粘连蛋白 111 蛋白治疗的功效。我们的结果表明，肌肉疾病发作后进行层粘连蛋白 111 治疗可延长预期寿命，促进肌肉生长并增加肌肉硬度。这些研究共同表明，在疾病过程的早期或晚期，层粘连蛋白 111 蛋白疗法可以作为 LAMA2-CMD 的有效蛋白替代疗法。
Laminin-alpha 2 related congenital muscular dystrophy (LAMA2-CMD) is a fatal muscle disease caused by mutations in the LAMA2 gene. Laminin-alpha 2 is critical for the formation of laminin-211 and -221 heterotrimers in the muscle basal lamina. LAMA2-CMD patients exhibit hypotonia from birth and progressive muscle loss that results in developmental delay, confinement to a wheelchair, respiratory insufficiency and premature death. There is currently no cure or effective treatment for LAMA2-CMD. Several studies have shown laminin-111 can serve as an effective protein-replacement therapy for LAMA2-CMD. Studies have demonstrated early treatment with laminin-111 protein results in an increase in life expectancy and improvements in muscle pathology and function. Since LAMA2-CMD patients are often diagnosed after advanced disease, it is unclear if laminin-111 protein therapy at an advanced stage of the disease can have beneficial outcomes. In this study, we tested the efficacy of laminin-111 protein therapy after disease onset in a mouse model of LAMA2-CMD. Our results showed laminin-111 treatment after muscle disease onset increased life expectancy, promoted muscle growth and increased muscle stiffness. Together these studies indicate laminin-111 protein therapy either early or late in the disease process could serve as an effective protein replacement therapy for LAMA2-CMD.