Abstract Details

Title Targeting the neuromuscular junction to treat congenital myasthenic syndromes and inherited motor neuropathies

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P3 - Poster Session 3 (12:00 PM-1:00 PM)

Poster/Presentation
Number 1-002

Objective We tested a novel compound, NT-1654 to improve neuromuscular transmission in mouse
models of human congenital myasthenic syndromes (CMS) (mice with mutations in the AGRN, COLQ and the DOK7 genes) and in a mouse model of hereditary motor neuropathy (GARS).

Background Disruption of the development and maintenance of the neuromuscular junction (NMJ) through mutations in the genes encoding its components lead to congenital myasthenic syndromes (CMS). 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 lead to hereditary motor neuropathies; and NMJ abnormalities have been demonstrated in genetic neuropathies. Current treatments for these conditions are limited and mainly symptomatic.

Design/Methods The development and maintenance of the NMJ critically depends on the agrin/LRP4/MuSK pathway, whereby an active neuronal form of agrin is secreted by the nerve terminal which binds to its receptor LRP4 on the muscle fibre surface. Neurotune, a Swiss biotech company, has developed a modified form of agrin (NT-1654) which is soluble and resistant to specific proteolysis. For each animal model wild type (WT), vehicle treated, and NT1654 treated animals were investigated, with treated animals receiving a daily subcutaneous injection of the drug at 10mg/Kg. At the end of the study animals were sacrificed and tissues taken.

Results Results varied by animal model with the strongest response being observed in the AGRN mouse, with many aspects of NMJ structure returning to WT levels. In addition a normalisation of the fibre type and an improvement in muscle strength was noted. GARS animals also benefited with improvements in NMJ structure noted.

Conclusions

Our data show that NT1654 is safe and improves neuromuscular transmission in these mice models, as measured by morphological analysis of the NMJ, biochemical and functional analysis of the muscle.

Authors/Disclosures
Hanns Lochmuller, MD, FAAN (Childrens Hospital of Eastern Ontario) PRESENTER	Dr. Lochmuller has received personal compensation in the range of $500-$4,999 for serving as a Consultant for CCRM. Dr. Lochmuller has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB Canada Inc. Dr. Lochmuller has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Lochmuller has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Satellos. Dr. Lochmuller has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for KYE Pharma. Dr. Lochmuller has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Lochmuller has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Satellos. Dr. Lochmuller has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi US. Dr. Lochmuller has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Santhera. Dr. Lochmuller has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Precision. Dr. Lochmuller has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis.
	No disclosure on file
	No disclosure on file
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Rita Horvath, MD (Jahn F Hospital, Dept Neurology)	No disclosure on file

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