Maternal delivery of a MuSK agonist antibody reveals a novel strategy for understanding and treating early-onset neuromuscular diseases

Congenital myasthenia (CM) comprises a group of neuromuscular diseases caused by mutations in genes responsible for the formation and function of neuromuscular synapses, including genes encoding neuronal Agrin, low-density receptor-related protein 4 (Lrp4), muscle-specific kinase (MuSK), downstream of kinase 7 (Dok7), and receptor-associated protein (Rapsyn). Although mouse models have been invaluable for studying neuromuscular diseases, including CM, early neonatal lethality, due to respiratory failure, has made it difficult to study disease progression or assess potential treatments. Previously, we demonstrated that postnatal delivery of a MuSK agonist antibody rescued neuromuscular synapses and prevented disease in a mouse model of Dok7 CM. To determine whether a MuSK agonist antibody could benefit other forms of CM, we delivered a MuSK agonist antibody to pregnant mice and thereby their progeny. Maternal delivery of a MuSK agonist antibody prevented neonatal lethality of Dok7 mutant mice, allowing the mice to survive for at least two months. Maternal delivery of a MuSK agonist antibody also rescued neuronal agrin mutant mice from neonatal lethality, but the mice failed to survive for two months, even after additional postnatal treatment with the agonist antibody. Partial and full denervation were prominent in rescued neuronal agrin mutant mice, suggesting that poor attachment and withdrawal of nerve terminals are responsible for their postnatal lethality. These findings indicate that neuronal Agrin has functions in synaptic differentiation and maintenance that are independent of MuSK activation. Classifications: Biological Sciences / Neuroscience.