DOK 7 gene therapy enhances motor activity and life span in ALS model mice

• Published in: EMBO molecular medicine Vol. 9; no. 7; pp. 880 - 889
• Main Authors: Miyoshi, Sadanori, Tezuka, Tohru, Arimura, Sumimasa, Tomono, Taro, Okada, Takashi, Yamanashi, Yuji
• Format: Journal Article
• Language: English
• Published: 01.07.2017
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201607298

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 ( NMJ s), 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 Mu SK by the cytoplasmic protein Dok‐7 is essential for NMJ formation, and forced expression of Dok‐7 in muscle activates Mu SK and enlarges NMJ s. Here, we show that therapeutic administration of an adeno‐associated virus vector encoding the human DOK 7 gene suppressed motor nerve terminal degeneration at NMJ s together with muscle atrophy in the SOD 1‐G93A ALS mouse model. Ultimately, we show that DOK 7 gene therapy enhanced motor activity and life span in ALS model mice. Synopsis image Forced expression of DOK 7 in muscle enlarges the neuromuscular junction ( NMJ ). Here, DOK 7 gene therapy suppresses NMJ degeneration and enhances motor activity and life span in a mouse model of ALS , a progressive motor neurodegenerative disease. DOK 7 gene therapy suppresses motor nerve terminal degeneration at the neuromuscular junction ( NMJ ) and muscle atrophy in ALS model mice. DOK 7 gene therapy prolongs lifespan and enhances motor activity in ALS model mice. DOK 7 gene therapy, or any equivalent method that stably and safely enlarges the NMJ , has potential for treating various motor neuron diseases that manifest NMJ defects.