Lama1 upregulation prolongs the lifespan of the dyH/dyH mouse model of LAMA2-related congenital muscular dystrophy.

LAMA2-related congenital muscular dystrophy (LAMA2-CMD), characterized by laminin-α2 deficiency, is debilitating and ultimately fatal. To date, no effective therapy has been clinically available. Laminin-α1, which shares significant similarities with laminin-α2, has been proven as a viable compensatory modifier. To evaluate its clinical applicability, we establish a Lama2 exon-3-deletion mouse model (dyH/dyH). The dyH/dyH mice exhibit early lethality and typical LAMA2-CMD phenotypes, allowing the evaluation of various endpoints. In dyH/dyH mice treated with synergistic activation mediator-based CRISPRa-mediated Lama1 upregulation, a nearly doubled median survival is observed, as well as improvements in weight and grip. Significant therapeutical effects are revealed by MRI, serum biochemical indices, and muscle pathology studies. Treating LAMA2-CMD with LAMA1 upregulation is feasible, and early intervention can alleviate symptoms and extend lifespan. Additionally, we reveal the limitations of LAMA1 upregulation, including high-dose mortality and non-sustained expression, which require further optimization in future studies. Copyright © 2024 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Ltd. All rights reserved.

Citation

Yidan Liu, Dandan Tan, Kaiyue Ma, Huaxia Luo, Jingping Mao, Jihang Luo, Qiang Shen, Luzheng Xu, Shiqi Yang, Lin Ge, Yuxuan Guo, Hong Zhang, Hui Xiong. Lama1 upregulation prolongs the lifespan of the dyH/dyH mouse model of LAMA2-related congenital muscular dystrophy. Journal of genetics and genomics = Yi chuan xue bao. 2024 Oct;51(10):1066-1078

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PMID: 38777118

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