Randomized controlled trial of N-acetylcysteine therapy for RYR1-related myopathies

Joshua J Todd, Tokunbor A Lawal, Jessica W Witherspoon, Irene C Chrismer, Muslima S Razaqyar, Monal Punjabi, Jeffrey S Elliott, Fatoumata Tounkara, Anna Kuo, Monique O Shelton, Carolyn Allen, Mary M Cosgrove, Melody Linton, Darren Michael, Minal S Jain, Melissa Waite, Bart Drinkard, Paul G Wakim, James J Dowling, Carsten G Bönnemann, Magalie Emile-Backer, Katherine G Meilleur, Joshua J Todd, Tokunbor A Lawal, Jessica W Witherspoon, Irene C Chrismer, Muslima S Razaqyar, Monal Punjabi, Jeffrey S Elliott, Fatoumata Tounkara, Anna Kuo, Monique O Shelton, Carolyn Allen, Mary M Cosgrove, Melody Linton, Darren Michael, Minal S Jain, Melissa Waite, Bart Drinkard, Paul G Wakim, James J Dowling, Carsten G Bönnemann, Magalie Emile-Backer, Katherine G Meilleur

Abstract

Objective: To investigate the efficacy of N-acetylcysteine (NAC) for decreasing elevated oxidative stress and increasing physical endurance in individuals with ryanodine receptor 1-related myopathies (RYR1-RM).

Methods: In this 6-month natural history assessment (n = 37) followed by a randomized, double-blinded, placebo-controlled trial, 33 eligible participants were block-randomized (1:1) to receive NAC (n = 16) or placebo (n = 17), orally for 6 months (adult dose 2,700 mg/d; pediatric dose 30 mg/kg/d). The primary endpoint was urine 15-F2t isoprostane concentration and the clinically meaningful co-primary endpoint was 6-minute walk test (6MWT) distance.

Results: When compared to the general population, participants had elevated baseline 15-F2t isoprostane concentrations and most had a decreased 6MWT distance (mean ± SD 3.2 ± 1.5 vs 1.1 ± 1.7 ng/mg creatinine and 468 ± 134 vs 600 ± 58 m, respectively, both p < 0.001). 15-F2t isoprostane concentration and 6MWT distance did not change over the 6-month natural history assessment (p = 0.98 and p = 0.61, respectively). NAC treatment did not improve 15-F2t isoprostane concentration (least squares means difference 0.1 [95% confidence interval [CI] -1.4 to 1.6] ng/mg creatinine, p = 0.88) or 6MWT distance (least squares means difference 24 [95% CI -5.5 to 53.4] m, p = 0.11). NAC was safe and well-tolerated at the doses administered in this study.

Conclusion: In ambulatory RYR1-RM-affected individuals, we observed stable disease course, and corroborated preclinical reports of elevated oxidative stress and decreased physical endurance. NAC treatment did not decrease elevated oxidative stress, as measured by 15-F2t isoprostane.

Classification of evidence: This study provides Class I evidence that, for people with RYR1-RM, treatment with oral NAC does not decrease oxidative stress as measured by 15-F2t isoprostane.

Clinicaltrialsgov identifier: NCT02362425.

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure. Consolidated Standards for Reporting Trial flow…
Figure. Consolidated Standards for Reporting Trial flow diagram
ITT = intent-to-treat; NAC = N-acetylcysteine.

References

    1. Amburgey K, McNamara N, Bennett LR, McCormick ME, Acsadi G, Dowling JJ. Prevalence of congenital myopathies in a representative pediatric United States population. Ann Neurol 2011;70:662–665.
    1. Todd JJ, Sagar V, Lawal TA, et al. . Correlation of phenotype with genotype and protein structure in RYR1-related disorders. J Neurol 2018;265:2506–2524.
    1. Amburgey K, Bailey A, Hwang JH, et al. . Genotype-phenotype correlations in recessive RYR1-related myopathies. Orphanet J Rare Dis 2013;8:117.
    1. Petrovski S, Wang Q, Heinzen EL, Allen AS, Goldstein DB. Genic intolerance to functional variation and the interpretation of personal genomes. PLoS Genet 2013;9:e1003709.
    1. Witherspoon JW, Meilleur KG. Review of RyR1 pathway and associated pathomechanisms. Acta Neuropathol Commun 2016;4:121.
    1. Dowling JJ, Arbogast S, Hur J, et al. . Oxidative stress and successful antioxidant treatment in models of RYR1-related myopathy. Brain 2012;135:1115–1127.
    1. Durham WJ, Aracena-Parks P, Long C, et al. . RyR1 S-nitrosylation underlies environmental heat stroke and sudden death in Y522S RyR1 knockin mice. Cell 2008;133:53–65.
    1. Lee CS, Hanna AD, Wang H, et al. . A chemical chaperone improves muscle function in mice with a RyR1 mutation. Nat Commun 2017;8:14659.
    1. Hardan AY, Fung LK, Libove RA, et al. . A randomized controlled pilot trial of oral N-acetylcysteine in children with autism. Biol Psychiatry 2012;71:956–961.
    1. Tirouvanziam R, Conrad CK, Bottiglieri T, Herzenberg LA, Moss RB, Herzenberg LA. High-dose oral N-acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis. Proc Natl Acad Sci USA 2006;103:4628–4633.
    1. Milne GL, Sanchez SC, Musiek ES, Morrow JD. Quantification of F2-isoprostanes as a biomarker of oxidative stress. Nat Protoc 2007;2:221–226.
    1. Müller F, Svardal AM, Nordoy I, Berge RK, Aukrust P, Frøland SS. Virological and immunological effects of antioxidant treatment in patients with HIV infection. Eur J Clin Invest 2000;30:905–914.
    1. van 't Erve TJ, Kadiiska MB, London SJ, Mason RP. Classifying oxidative stress by F(2)-isoprostane levels across human diseases: a meta-analysis. Redox Biol 2017;12:582–599.
    1. Evans S. When and how can endpoints be changed after initiation of a randomized clinical trial? PLoS Clin Trials 2007;2:e18.
    1. Witherspoon JW, Vasavada RP, Waite MR, et al. . 6-minute walk test as a measure of disease progression and fatigability in a cohort of individuals with RYR1-related myopathies. Orphanet J Rare Dis 2018;13:105.
    1. Jones DP, Carlson JL, Mody VC, Cai J, Lynn MJ, Sternberg P. Redox state of glutathione in human plasma. Free Radic Biol Med 2000;28:625–635.
    1. Enright PL, Sherrill DL. Reference equations for the six-minute walk in healthy adults. Am J Respir Crit Care Med 1998;158:1384–1387.
    1. Geiger R, Strasak A, Treml B, et al. . Six-minute walk test in children and adolescents. J Pediatr 2007;150:395–399.
    1. Klepper SE, Muir N. Reference values on the 6-minute walk test for children living in the United States. Pediatr Phys Ther 2011;23:32–40.
    1. Todd JJ, Razaqyar MS, Witherspoon JW, et al. . Novel variants in individuals with RYR1-related congenital myopathies: genetic, laboratory, and clinical findings. Front Neurol 2018;9:118.
    1. Horowitz JD, Henry CA, Syrjanen ML, et al. . Nitroglycerine/N-acetylcysteine in the management of unstable angina pectoris. Eur Heart J 1988;9 suppl A:95–100.
    1. Heckbert SR, Wiggins KL, Glazer NL, et al. . Antihypertensive treatment with ACE inhibitors or beta-blockers and risk of incident atrial fibrillation in a general hypertensive population. Am J Hypertens 2009;22:538–544.
    1. Girouard H, Chulak C, Wu L, Lejossec M, de Champlain J. N-acetylcysteine improves nitric oxide and alpha-adrenergic pathways in mesenteric beds of spontaneously hypertensive rats. Am J Hypertens 2003;16:577–584.
    1. Milne GL, Dai Q, Roberts LJ II. The isoprostanes: 25 years later. Biochim Biophys Acta 2015;1851:433–445.
    1. Lamont PJ, Dubowitz V, Landon DN, Davis M, Morgan-Hughes JA. Fifty year follow-up of a patient with central core disease shows slow but definite progression. Neuromuscul Disord 1998;8:385–391.
    1. Paschalis V, Theodorou AA, Margaritelis NV, Kyparos A, Nikolaidis MG. N-acetylcysteine supplementation increases exercise performance and reduces oxidative stress only in individuals with low levels of glutathione. Free Radic Biol Med 2018;115:288–297.
    1. Medved I, Brown MJ, Bjorksten AR, et al. . N-acetylcysteine enhances muscle cysteine and glutathione availability and attenuates fatigue during prolonged exercise in endurance-trained individuals. J Appl Physiol 2004;97:1477–1485.
    1. Holdiness MR. Clinical pharmacokinetics of N-acetylcysteine. Clin Pharmacokinet 1991;20:123–134.
    1. Bohannon RW, Crouch R. Minimal clinically important difference for change in 6-minute walk test distance of adults with pathology: a systematic review. J Eval Clin Pract 2017;23:377–381.
    1. Mori TA, Puddey IB, Burke V, et al. . Effect of omega 3 fatty acids on oxidative stress in humans: GC-MS measurement of urinary F2-isoprostane excretion. Redox Rep 2000;5:45–46.
    1. McGlory C, Galloway SD, Hamilton DL, et al. . Temporal changes in human skeletal muscle and blood lipid composition with fish oil supplementation. Prostaglandins, Leukot Essent fatty Acids 2014;90:199–206.
    1. De Felice C, Signorini C, Durand T, et al. . Partial rescue of Rett syndrome by ω-3 polyunsaturated fatty acids (PUFAs) oil. Genes Nutr 2012;7:447–458.
    1. Honen BN, Saint DA, Laver DR. Suppression of calcium sparks in rat ventricular myocytes and direct inhibition of sheep cardiac RyR channels by EPA, DHA and oleic acid. J Membr Biol 2003;196:95–103.
    1. Zhao H, Li H, Hao S, et al. . Peptide SS-31 upregulates frataxin expression and improves the quality of mitochondria: implications in the treatment of Friedreich ataxia. Sci Rep 2017;7:9840.

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