北京大学Hui Xiong等研究人员合作发现，Lama1上调可延长LAMA2相关先天性肌营养不良症dy^H/dy^H小鼠模型的寿命。2024年5月21日，国际知名学术期刊《遗传学报》在线发表了这一成果。

研究人员表示，LAMA2相关先天性肌营养不良症（LAMA2-CMD）以缺乏层粘连蛋白-α2为特征，会使人衰弱，最终导致死亡。迄今为止，临床上尚无有效的治疗方法。层粘连蛋白-α1与层粘连蛋白-α2有着显著的相似性，已被证明是一种可行的代偿调节剂。

附：英文原文

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

Author: Yuxuan Guo b, Hong Zhang b, Hui Xiong a g

Issue&Volume: 2024/05/21

Abstract: 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 (SAM)-based CRISPRa-mediated Lama1 upregulation (total dose: 1.0 × 1011 vector genomes/mouse), a nearly doubled median survival is observed, as well as improvements in weight and grip. Significant therapeutical effects are also demonstrated in MRI, serum biochemical indices, and muscle pathology studies. We show that treating LAMA2-CMD with LAMA1 upregulation is feasible and that early intervention can alleviate symptoms and extend lifespan. Additionally, we reveal limitations of LAMA1 upregulation, including high-dose mortality and non-sustained expression, which require further optimization in future studies.

DOI: 10.1016/j.jgg.2024.05.005

Source: https://www.sciencedirect.com/science/article/abs/pii/S1673852724001188