PMID- 37637210
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230829
IS  - 2162-2531 (Print)
IS  - 2162-2531 (Electronic)
IS  - 2162-2531 (Linking)
VI  - 33
DP  - 2023 Sep 12
TI  - Long-term muscle-specific overexpression of DOK7 in mice using AAV9-tMCK-DOK7.
PG  - 617-628
LID - 10.1016/j.omtn.2023.07.036 [doi]
AB  - Neuromuscular junction (NMJ) dysfunction underlies several diseases, including 
      congenital myasthenic syndromes (CMSs) and motor neuron disease (MND). Molecular 
      pathways governing NMJ stability are therefore of interest from both biological 
      and therapeutic perspectives. Muscle-specific kinase (MuSK) is necessary for the 
      formation and maintenance of post-synaptic elements of the NMJ, and downstream of 
      tyrosine kinases 7 (DOK7) is crucial for activation of the MuSK pathway. 
      Overexpression of DOK7 using AAV9 has been shown to ameliorate neuromuscular 
      pathology in pre-clinical disease models of CMS and MND. However, long-term 
      consequences of DOK7 expression have been sparsely investigated and targeted 
      overexpression of DOK7 in skeletal muscle yet to be established. Here, we 
      developed and characterized a novel AAV9-DOK7 facilitating forced expression of 
      DOK7 under a skeletal muscle-specific promoter. AAV9-tMCK-DOK7 was systemically 
      delivered to newborn mice that were monitored over 6 months. DOK7 overexpression 
      was restricted to skeletal muscles. Body weight, blood biochemistry, and 
      histopathological assessments were unaffected by AAV9-tMCK-DOK7 treatment. In 
      contrast, forced expression of DOK7 resulted in enlargement of both the pre- and 
      post-synaptic components of the NMJ, without causing denervation. We conclude 
      that muscle-specific DOK7 overexpression can be achieved in a safe manner, with 
      the capacity to target NMJs in vivo.
CI  - (c) 2023 The Author(s).
FAU - Huang, Yu-Ting
AU  - Huang YT
AD  - Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Edinburgh 
      EH16 4SB, UK.
AD  - Euan MacDonald Centre for Motor Neuron Disease Research, Edinburgh EH16 4SB, UK.
FAU - Crick, Hannah R
AU  - Crick HR
AD  - Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Edinburgh 
      EH16 4SB, UK.
AD  - Euan MacDonald Centre for Motor Neuron Disease Research, Edinburgh EH16 4SB, UK.
FAU - Chaytow, Helena
AU  - Chaytow H
AD  - Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Edinburgh 
      EH16 4SB, UK.
AD  - Euan MacDonald Centre for Motor Neuron Disease Research, Edinburgh EH16 4SB, UK.
FAU - van der Hoorn, Dinja
AU  - van der Hoorn D
AD  - Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Edinburgh 
      EH16 4SB, UK.
AD  - Euan MacDonald Centre for Motor Neuron Disease Research, Edinburgh EH16 4SB, UK.
FAU - Alhindi, Abrar
AU  - Alhindi A
AD  - Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Edinburgh 
      EH16 4SB, UK.
AD  - Euan MacDonald Centre for Motor Neuron Disease Research, Edinburgh EH16 4SB, UK.
AD  - Faculty of Medicine, Department of Anatomy, King Abdulaziz University, Jeddah 
      21589, Saudi Arabia.
FAU - Jones, Ross A
AU  - Jones RA
AD  - Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Edinburgh 
      EH16 4SB, UK.
AD  - Euan MacDonald Centre for Motor Neuron Disease Research, Edinburgh EH16 4SB, UK.
FAU - Hector, Ralph D
AU  - Hector RD
AD  - Neurogene Inc, 535 W 24th St, New York, NY 10011, USA.
FAU - Cobb, Stuart R
AU  - Cobb SR
AD  - Neurogene Inc, 535 W 24th St, New York, NY 10011, USA.
FAU - Gillingwater, Thomas H
AU  - Gillingwater TH
AD  - Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Edinburgh 
      EH16 4SB, UK.
AD  - Euan MacDonald Centre for Motor Neuron Disease Research, Edinburgh EH16 4SB, UK.
LA  - eng
PT  - Journal Article
DEP - 20230802
PL  - United States
TA  - Mol Ther Nucleic Acids
JT  - Molecular therapy. Nucleic acids
JID - 101581621
PMC - PMC10457688
OTO - NOTNLM
OT  - AAV9
OT  - DOK7
OT  - MT: Delivery strategies
OT  - NMJ
OT  - gene therapy
OT  - mouse
OT  - neuromuscular junction
COIS- Commercial funding for this study was provided by NeuroGene (to T.H.G). T.H.G. 
      has served on advisory boards for Roche, Novartis, LifeArc, and SMA Europe. 
      R.D.H. and S.R.C. are consultants at Neurogene Inc.
EDAT- 2023/08/28 06:42
MHDA- 2023/08/28 06:43
PMCR- 2023/08/02
CRDT- 2023/08/28 04:45
PHST- 2023/04/04 00:00 [received]
PHST- 2023/07/31 00:00 [accepted]
PHST- 2023/08/28 06:43 [medline]
PHST- 2023/08/28 06:42 [pubmed]
PHST- 2023/08/28 04:45 [entrez]
PHST- 2023/08/02 00:00 [pmc-release]
AID - S2162-2531(23)00209-3 [pii]
AID - 10.1016/j.omtn.2023.07.036 [doi]
PST - epublish
SO  - Mol Ther Nucleic Acids. 2023 Aug 2;33:617-628. doi: 10.1016/j.omtn.2023.07.036. 
      eCollection 2023 Sep 12.