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

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Science  19 Sep 2014:
Vol. 345, Issue 6203, pp. 1505-1508
DOI: 10.1126/science.1250744

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Building connections by gene therapy

Voluntary movement requires a molecular conversation between nerves and muscles. This conversation occurs at the neuromuscular junction, a structure where nerves and muscle physically connect. People with diseases characterized by muscle weakness have aberrantly small neuromuscular junctions. Arimura et al. used gene therapy to enlarge the neuromuscular junction, which made muscles stronger. Studying mouse models of two distinct neuromuscular disorders, they used an adenovirus vector to deliver DOK7, a gene required for formation of the neuromuscular junction. The therapy improved the mice's motor activity and life span.

Science, this issue p. 1505


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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