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Science. 2014 Sep 19;345(6203):1505-8. doi: 10.1126/science.1250744.

Neuromuscular disease. DOK7 gene therapy benefits mouse models of diseases characterized by defects in the neuromuscular junction.

Author information

1
Division of Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
2
Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
3
Department of Occupational Therapy, Nagasaki University School of Health Sciences, Nagasaki, Japan.
4
Department of Electrical and Electronics Engineering, Faculty of Engineering, Nagasaki Institute of Applied Science, Nagasaki, Japan.
5
Laboratory of Developmental Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
6
Neurosciences Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
7
Division of Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. yyamanas@ims.u-tokyo.ac.jp.

Abstract

The neuromuscular junction (NMJ) is the synapse between a motor neuron and skeletal muscle. Defects in NMJ transmission cause muscle weakness, termed myasthenia. The muscle protein Dok-7 is essential for activation of the receptor kinase MuSK, which governs NMJ formation, and DOK7 mutations underlie familial limb-girdle myasthenia (DOK7 myasthenia), a neuromuscular disease characterized by small NMJs. Here, we show in a mouse model of DOK7 myasthenia that therapeutic administration of an adeno-associated virus (AAV) vector encoding the human DOK7 gene resulted in an enlargement of NMJs and substantial increases in muscle strength and life span. When applied to model mice of another neuromuscular disorder, autosomal dominant Emery-Dreifuss muscular dystrophy, DOK7 gene therapy likewise resulted in enlargement of NMJs as well as positive effects on motor activity and life span. These results suggest that therapies aimed at enlarging the NMJ may be useful for a range of neuromuscular disorders.

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PMID:
25237101
DOI:
10.1126/science.1250744
[Indexed for MEDLINE]
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