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

Science 19 September 2014: 1505-1508. [DOI:10.1126/science.1250744]

Sumimasa Arimura1, Takashi Okada2, Tohru Tezuka1, Tomoko Chiyo2, Yuko Kasahara2, Toshiro Yoshimura3, Masakatsu Motomura4, Nobuaki Yoshida5, David Beeson6, Shin'ichi Takeda2, Yuji Yamanashi1

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

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.

List: Scientific Papers/Award