Wellcome Trust Funded Project in CMS

Strengthening the neuromuscular junction as a new concept for the treatment of congenital myasthenic syndromes and motor neuropathies with synaptic dysfunction

Disruption of the development and maintenance of the neuromuscular junction (NMJ) through mutations in the genes encoding its components or auto-antibodies against its elements lead to congenital myasthenic syndromes (CMS) and acquired myasthenia gravis (MG) respectively. These disorders result in impaired neurotransmission, and fatigable muscle weakness. The phenotypical spectrum of NMJ dysfunction is expanding; several recently identified mutations in presynaptic NMJ proteins have been shown to cause hereditary motor neuropathies, and NMJ abnormalities have been demonstrated in genetic neuropathies. Current treatments for these conditions are limited in that they are mainly symptomatic and limited by systemic side-effects.

Development and maintenance of the NMJ critically depends on the neuronal factor agrin, and the agrin/LRP4/MuSK pathway. The naturally occurring form of agrin is highly insoluble and its activity is counteracted by cleavage by a specific serine protease (neurotrypsin). Neurotune AG, a Swiss biotech company, has developed a modified form of agrin (NT-1654) which is soluble and resistant to specific proteolysis. Through a Pathfinder Award, Professor Lochmüller and colleagues at Newcastle University will test the effect of NT-1654 in mouse models of human CMS and in a mouse model of hereditary motor neuropathy. The team aim to provide evidence that NT-1654 improves neuromuscular transmission in these mouse models and to identify the pharmacokinetic properties and molecular mechanisms of this improvement, thus providing further evidence for its use as a therapeutic reagent in clinical trials (Source: Wellcome Trust Pathfinder Awards).