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A muscle-targeted AAV9 confers long-term overexpression of DOK7 in mice

Y -T Huang(1,2) H R Crick(1,2) H Chaytow(1,2) D van der Hoorn(1,2) A Alhindi(1,2,3) R A Jones(1,2) R D Hector(4) S R Cobb(4) T H Gillingwater(1,2)

1:Edinburgh Medical School: Biomedical Sciences, University of Edinburgh; Edinburgh, UK; 2:Euan MacDonald Centre for Motor Neuron Disease Research; Edinburgh, UK; 3:Faculty of Medicine, Department of Anatomy, King Abdulaziz University; Jeddah, Saudi Arabia; 4:Neurogene Inc, 535 W 24th St, New York, NY, USA

Intention becomes action where motor nerves meet muscle: the neuromuscular junction. Disjunction of these synapses underlies numerous diseases including congenital myasthenic syndromes (CMSs) and motor neuron diseases (MNDs), creating an area of therapeutic interest around the molecular pathways that govern neuromuscular junction (NMJ) stability. Several studies have shown that increasing expression of the NMJ stabilising protein Docking protein 7 (DOK7) via AAV9-based therapy can confer short-term benefits including regeneration of NMJs in models of neuromuscular disease, however this has been achieved under the control of the ubiquitous cytomegalovirus promoter.

We demonstrated that an AAV9-based therapy, targeted to skeletal muscle via the triple tandem modified muscle creatine kinase (tMCK) promoter, can instigate long-term, specific elevation of DOK7 protein in skeletal muscle. This resulted in enlargement of the pre-and post-synaptic compartments of the NMJ without affecting innervation, bodyweight, blood biochemistry, or untargeted organs, as examined by histopathology. This demonstrates a method by which gene-therapy targeted to the muscle can impact retrograde transport across the NMJ to help anchor the neuronal terminal to the muscle long-term, without the need to target motor neurons. We conclude that muscle-specific overexpression of DOK7 can be achieved safely, with the capacity to target NMJs in vivo.

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