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

doi:10.1016/j.jgg.2024.05.005

Volume 51 Issue 10

Oct. 2024

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Article Navigation > Journal of Genetics and Genomics > 2024 > 51(10): 1066-1078

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Lama1 upregulation prolongs the lifespan of the dy^H/dy^H mouse model of LAMA2-related congenital muscular dystrophy

doi: 10.1016/j.jgg.2024.05.005

a. Department of Pediatrics, Peking University First Hospital, Beijing 102600, China;
b. 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;
c. Department of Neurology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, China;
d. Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200030, China;
e. Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA;
f. Medical and Health Analysis Center, Peking University, Beijing 100191, China;
g. Department of Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China

Funds:

This study received support from the following grants: National Natural Science Foundation of China (82171393 to H.X.), National High Level Hospital Clinical Research Funding (High Quality Clinical Research Project of Peking University First Hospital) (2022CR69 to H.X.), Natural Science Foundation of Beijing Municipality (7212116 to H.X.), National Key Research and Development Program of China (2016YFC0901505 to H.X.), Beijing Key Laboratory of Molecular Diagnosis and Study on Pediatric Genetic Diseases (BZ0317 to H.X.), Research Foundation for Youth Talents of the First Affiliated Hospital of Nanchang University (YFYPY202223 to D.T.), and Natural Science Foundation of Beijing Municipality (7242149 to H.L.).

Received Date: 2024-05-12
Accepted Date: 2024-05-18
Rev Recd Date: 2024-05-17

Available Online: 2025-06-06

Publish Date: 2024-05-21

Abstract

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 (dy^H/dy^H). The dy^H/dy^H mice exhibit early lethality and typical LAMA2-CMD phenotypes, allowing the evaluation of various endpoints. In dy^H/dy^H 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.
- Disease model,
- Gene therapy,
- CRISPRa,
- Congenital muscular dystrophy,
- LAMA2

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References(57)

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