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

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外文摘要：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.

外文关键词：

Disease modelGene therapyCRISPRaCongenital muscular dystrophyLAMA2

作者：

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

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作者单位：

Department of Pediatrics,Peking University First Hospital,Beijing 102600,China

State Key Laboratory of Vascular Homeostasis and Remodeling,The Institute of Cardiovascular Sciences,School of Basic Medical Sciences,Peking University Health Science Center,Beijing 100191,China

Department of Neurology,The First Affiliated Hospital,Jiangxi Medical College,Nanchang University,Nanchang,Jiangxi 330006,China

Bio-X Institutes,Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders,Ministry of Education,Shanghai Jiao Tong University,Shanghai 200030,China

Department of Genetics,Yale School of Medicine,New Haven,CT 06510,USA

Medical and Health Analysis Center,Peking University,Beijing 100191,China

Department of Neurology,Beijing Children's Hospital,Capital Medical University,National Center for Children's Health,Beijing 100045,China

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基金：

National Natural Science Foundation of ChinaNational High Level Hospital Clinical Research Funding(High Quality Clinical Research Project of Peking University First HospitaNatural Science Foundation of Beijing MunicipalityNational Key Research and Development Program of ChinaBeijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic DiseasesResearch Foundation for Youth Talents of the First Affiliated Hospital of Nanchang UniversityNatural Science Foundation of Beijing Municipality

项目编号：

821713932022CR6972121162016YFC0901505BZ0317YFYPY2022237242149

出版年：

2024

DOI：

10.1016/j.jgg.2024.05.005

遗传学报

中国遗传学会中国科学院遗传与发育生物学研究所

遗传学报

CSTPCD

影响因子：0.821

ISSN：1673-8527

年,卷(期)：2024.51(10)