DOK7 Gene Therapy Enhances Neuromuscular Junction Innervation and Motor Function in Aged Mice

Ryo Ueta; Satoshi Sugita; Yoshihiko Minegishi; Akira Shimotoyodome; Noriyasu Ota; Noboru Ogiso; Takahiro Eguchi; Yuji Yamanashi

doi:10.1016/j.isci.2020.101385

DOK7 Gene Therapy Enhances Neuromuscular Junction Innervation and Motor Function in Aged Mice

iScience. 2020 Aug 21;23(8):101385. doi: 10.1016/j.isci.2020.101385. Epub 2020 Aug 5.

Authors

Ryo Ueta¹, Satoshi Sugita², Yoshihiko Minegishi², Akira Shimotoyodome², Noriyasu Ota², Noboru Ogiso³, Takahiro Eguchi⁴, Yuji Yamanashi⁵

Affiliations

¹ Division of Genetics, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
² Biological Science Research, Kao Corporation, 2606 Akabane, Ichikai-machi, Haga-gun, Tochigi 321-3497, Japan.
³ Laboratory of Experimental Animals, The National Center for Geriatrics and Gerontology, 7-430, Morioka-cho, Obu, Aichi 474-8511, Japan.
⁴ Division of Genetics, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Electronic address: teguchi@ims.u-tokyo.ac.jp.
⁵ Division of Genetics, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Electronic address: yyamanas@ims.u-tokyo.ac.jp.

Abstract

Muscle denervation at the neuromuscular junction (NMJ), the essential synapse between motor neuron and skeletal muscle, is associated with age-related motor impairment. Therefore, improving muscle innervation at aged NMJs may be an effective therapeutic strategy for treating the impairment. We previously demonstrated that the muscle protein Dok-7 plays an essential role in NMJ formation, and, indeed, its forced expression in muscle enlarges NMJs. Moreover, therapeutic administration of an adeno-associated virus vector encoding human Dok-7 (DOK7 gene therapy) suppressed muscle denervation and enhanced motor activity in a mouse model of amyotrophic lateral sclerosis (ALS). Here, we show that DOK7 gene therapy significantly enhances motor function and muscle strength together with NMJ innervation in aged mice. Furthermore, the treated mice showed greatly increased compound muscle action potential (CMAP) amplitudes compared with the controls, suggesting enhanced neuromuscular transmission. Thus, therapies aimed at enhancing NMJ innervation have potential for treating age-related motor impairment.

Keywords: Clinical Genetics; Molecular Mechanism of Gene Regulation; Musculoskeletal Medicine.