Abstract Details

Title Breaking the sound barrier of randomized, controlled trials in congenital myopathies: results of the N-acetylcysteine trial in RYR1-related disorders

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S23 - Genetic Muscle Disorders (4:03 PM-4:14 PM)

Poster/Presentation
Number 004

Background RYR1-related disorders (RYR1-RD) are rare, genetic neuromuscular disorders associated with variable expressivity of symptoms. RYR1 variants affect functionality of the major skeletal muscle calcium channel, ryanodine receptor type 1, and result in intracellular calcium dysregulation and downstream, excessive reactive oxygen species (ROS). An FDA-approved antioxidant, NAC, has been used to successfully ameliorate excessive ROS in three ��۸�1-RD preclinical models and improved swim endurance (relatively relaxed zebrafish) and muscle force (Y522S mice).

Objective This study tested the efficacy of N-acetylcysteine (NAC) in individuals affected with RYR1-related disorders.

Design/Methods Affected individuals (n=53) were enrolled in a double-blind, randomized controlled trial of NAC (2700mg/day or placebo for six-months) at the National Institutes of Health. ROS were assessed via urine 15-F2t isoprostane and endurance via six-minute walk tests (6MWT) pre- and post-intervention.

Results Prior to NAC, participants exhibited increased ROS with a 2.9-fold higher 15-F2t isoprostane concentration compared to controls (n=35, 3.2±1.4 ng/mg Cr vs. n=1881, 1.1±1.7 ng/mg Cr respectively, p< 0.001) and walked 79% of predicted norms during 6MWT (p< 0.001). There was no improvement in 15-F2t isoprostane concentration in response to NAC treatment (p=0.50). In those allocated to NAC, 6MWT distance did approach a clinically meaningful improvement of 24m (MCID for RYR1-RD, 25-83m) however this did not reach statistical significance (p=0.11).

Conclusions In RYR1-RD, ROS is elevated, and endurance is decreased compared to controls. NAC treatment did not decisively impact ROS or endurance.

Authors/Disclosures
Katherine G. Meilleur, PhD, PPCNP-BC (National Institutes of Health) PRESENTER	No disclosure on file
	No disclosure on file
Jessica Witherspoon	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Jeff Elliott	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
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	No disclosure on file
Tanya J. Lehky, MD (National Institutes of Health)	Dr. Lehky has nothing to disclose.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
James Dowling, MD, PhD (Hospital for Sick Children)	Dr. Dowling has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GLG. Dr. Dowling has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ikaika Therapeutics. Dr. Dowling has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bain Consulting. Dr. Dowling has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Guidepoint. Dr. Dowling has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for RYR1 Foundation. Dr. Dowling has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Dechert LLP. The institution of Dr. Dowling has received research support from Astellas. The institution of Dr. Dowling has received research support from NIH. The institution of Dr. Dowling has received research support from CIHR. The institution of Dr. Dowling has received research support from Astellas. Dr. Dowling has received personal compensation in the range of $5,000-$9,999 for serving as a advisor with Ontario Ministry of Health.
Carsten G. Bonnemann, MD	Dr. Bonnemann has a non-compensated relationship as a Scientific Advisor with RYR1 Foundation that is relevant to AAN interests or activities. Dr. Bonnemann has a non-compensated relationship as a Scientific Advisor with Genethon that is relevant to AAN interests or activities. Dr. Bonnemann has a non-compensated relationship as a Scientific Advisor with Sarepta Therapeutics that is relevant to AAN interests or activities. Dr. Bonnemann has a non-compensated relationship as a Scientific Advisor with Kate Therapeutics that is relevant to AAN interests or activities. Dr. Bonnemann has a non-compensated relationship as a Scientific Advisor with CureCMD that is relevant to AAN interests or activities. Dr. Bonnemann has a non-compensated relationship as a Scientific Advisor with Seal Therapeutics that is relevant to AAN interests or activities.
	No disclosure on file

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