Abstract Details

Title Improving NMJ Transmission Fidelity: An Additional Target in SMA?

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P7 - Poster Session 7 (5:30 PM-6:30 PM)

Poster/Presentation
Number 1-009

Objective To investigate neuromuscular junction transmission (NMJ) defects in a mouse model of symptomatically-treated spinal muscular atrophy (SMA).

Background

SMA is an autosomal recessive motor neuron disorder caused by low levels of SMN protein. There are two clinically-available treatments for SMN restoration, and preclinical and early clinical data strongly suggest that the effects of SMN restoration on the SMA phenotype are time-dependent. We hypothesized that NMJ transmission defects may persist following delayed SMN restoration.

Design/Methods Symptomatic SMA mice (Delta 7 model) were treated at 4 days of age with antisense oligonucleotides (delivered by intracerebroventricular injection) that target the intronic splicing silencer N1 to increase SMN protein. At P30, treated SMA mice were compared with healthy control mice using repetitive nerve stimulation of the sciatic nerve while recording compound muscle action potential decrement to investigate NMJ transmission defects. Rotarod was performed to determine if NMJ transmission defects were associated with impaired motor function.

Results At P30, symptomatic treated SMA mice (n=8) demonstrate significantly increased CMAP decrement compared with untreated, heterozygous control mice (n=6) (p<0.0001). CMAP amplitude was significantly reduced in the SMA mice (36±9 mV) compared with controls (50±7mV) (p=0.0099). Performance on rotarod was significantly correlated with CMAP amplitude (r=0.731, p=0.039). Rotarod variability (an assessment of fatigability between trials) was significantly increased in SMA versus control mice. Longitudinal studies are ongoing to understand progression of phenotype in symptomatic treated SMA mice.

Conclusions Exciting progress in the field of SMA has brought two SMN restoring therapies to the clinic with other SMN-restoring therapies in development. Our current studies suggest that NMJ transmission defects may be an additional target for management of muscle weakness and fatigue in SMA patients. Future studies can use this model of symptomatic treated SMA to investigate potential strategies for modulation of NMJ transmission as treatments for SMA.

Authors/Disclosures
Greg Owendoff PRESENTER	Greg Owendoff has nothing to disclose.
	No disclosure on file
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	No disclosure on file
Arthur H. Burghes, MD (Ohio State University)	No disclosure on file
William D. Arnold, MD	Dr. Arnold has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Arnold has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for La Hoffmann Roche. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cadent Therapeutics . Dr. Arnold has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. The institution of Dr. Arnold has received research support from NIH. The institution of Dr. Arnold has received research support from NMD Pharma. The institution of Dr. Arnold has received research support from Gilead Sciences. The institution of Dr. Arnold has received research support from CureSMA. Dr. Arnold has received intellectual property interests from a discovery or technology relating to health care.

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Abstract Details