遗传学报2024，Vol.51Issue(10) ：1066-1078.DOI:10.1016/j.jgg.2024.05.005

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

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
遗传学报2024，Vol.51Issue(10) ：1066-1078.DOI:10.1016/j.jgg.2024.05.005
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  • 万方数据

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

Yidan Liu 1Dandan Tan 2Kaiyue Ma 3Huaxia Luo 4Jingping Mao 5Jihang Luo 1Qiang Shen 5Luzheng Xu 6Shiqi Yang 1Lin Ge 7Yuxuan Guo 5Hong Zhang 5Hui Xiong8
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作者信息

  • 1. 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
  • 2. Department of Pediatrics,Peking University First Hospital,Beijing 102600,China;Department of Neurology,The First Affiliated Hospital,Jiangxi Medical College,Nanchang University,Nanchang,Jiangxi 330006,China
  • 3. 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
  • 4. Department of Pediatrics,Peking University First Hospital,Beijing 102600,China
  • 5. 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
  • 6. Medical and Health Analysis Center,Peking University,Beijing 100191,China
  • 7. Department of Genetics,Yale School of Medicine,New Haven,CT 06510,USA;Department of Neurology,Beijing Children's Hospital,Capital Medical University,National Center for Children's Health,Beijing 100045,China
  • 8. Department of Pediatrics,Peking University First Hospital,Beijing 102600,China;Department of Neurology,Beijing Children's Hospital,Capital Medical University,National Center for Children's Health,Beijing 100045,China
  • 折叠

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-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.

Key words

Disease model/Gene therapy/CRISPRa/Congenital muscular dystrophy/LAMA2

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基金项目

National Natural Science Foundation of China(82171393)

National High Level Hospital Clinical Research Funding(High Quality Clinical Research Project of Peking University First Hospita(2022CR69)

Natural Science Foundation of Beijing Municipality(7212116)

National Key Research and Development Program of China(2016YFC0901505)

Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases(BZ0317)

Research Foundation for Youth Talents of the First Affiliated Hospital of Nanchang University(YFYPY202223)

Natural Science Foundation of Beijing Municipality(7242149)

出版年

2024
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

CSTPCDCSCD
影响因子：0.821
ISSN：1673-8527
参考文献量57
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