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EMBO Mol Med. 2017 Jul;9(7):880-889. doi: 10.15252/emmm.201607298.

DOK7 gene therapy enhances motor activity and life span in ALS model mice.

Author information

1
Division of Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
2
Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan.
3
Graduate School of Comprehensive Human Sciences, Majors in Medical Sciences University of Tsukuba, Ibaraki, Japan.
4
Division of Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan yyamanas@ims.u-tokyo.ac.jp.

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive, multifactorial motor neurodegenerative disease with severe muscle atrophy. The glutamate release inhibitor riluzole is the only medication approved by the FDA, and prolongs patient life span by a few months, testifying to a strong need for new treatment strategies. In ALS, motor neuron degeneration first becomes evident at the motor nerve terminals in neuromuscular junctions (NMJs), the cholinergic synapse between motor neuron and skeletal muscle; degeneration then progresses proximally, implicating the NMJ as a therapeutic target. We previously demonstrated that activation of muscle-specific kinase MuSK by the cytoplasmic protein Dok-7 is essential for NMJ formation, and forced expression of Dok-7 in muscle activates MuSK and enlarges NMJs. Here, we show that therapeutic administration of an adeno-associated virus vector encoding the human DOK7 gene suppressed motor nerve terminal degeneration at NMJs together with muscle atrophy in the SOD1-G93A ALS mouse model. Ultimately, we show that DOK7 gene therapy enhanced motor activity and life span in ALS model mice.

KEYWORDS:

DOK7 ; amyotrophic lateral sclerosis; gene therapy; neuromuscular junction

PMID:
28490573
PMCID:
PMC5494517
DOI:
10.15252/emmm.201607298
[Indexed for MEDLINE]
Free PMC Article

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