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Neuromuscular Disorders

Oral N-acetylcysteine Trial for RYR1-related Myopathies

Author:

Vamshi Rao

Division of Neurology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL; Departments of Pediatrics and Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, US
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Abstract

Investigators from NIH, Hyperion Biotechnology Inc., and Hospital for Sick Children studied the effect of oral N-acetylcysteine (NAC) on decreasing oxidative stress and increasing physical endurance in individuals with ryanodine receptor 1-related myopathies (RYR1-RM).
How to Cite: Rao, V., 2022. Oral N-acetylcysteine Trial for RYR1-related Myopathies. Pediatric Neurology Briefs, 36, p.4. DOI: http://doi.org/10.15844/pedneurbriefs-36-4
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  Published on 30 Dec 2022
 Accepted on 21 Dec 2020            Submitted on 14 Dec 2020

Investigators from NIH, Hyperion Biotechnology Inc., and Hospital for Sick Children studied the effect of oral N-acetylcysteine (NAC) on decreasing oxidative stress and increasing physical endurance in individuals with ryanodine receptor 1-related myopathies (RYR1-RM).

The trial design included a selection of 37 genetically confirmed ambulatory individuals (adult and pediatric) with mild to moderate RYR1-RM phenotype. They were tracked as a part of natural history for six months, after which 33 of them were subsequently randomized (1:1) to a double-blinded, placebo-controlled trial. They either received a placebo (n = 17) or oral NAC (n=16) for six months. Primary endpoints were the evaluation of oxidative stress as measured by urine 15-F2t isoprostane concentration and physical endurance by the 6-minute walk test (6MWT) distance.

At baseline, individuals with RYR1-RM, in comparison to the general population, had a significantly (p<0.001) elevated mean 15-F2t isoprostane level (3.2 ± 1.5 vs 1.1 ± 1.7 ng/mg creatinine) and a decreased 6MWT distance (468 ± 134 vs 600 ± 58 m). Trial results showed no significant change of either 15-F2t isoprostane levels ((p = 0.98) or 6MWT distance (p = 0.61) during the 6-month natural history interval. Furthermore, in the NAC treatment group, there was no significant change in the 15-F2t isoprostane levels (p = 0.88) or 6MWT distance (p = 0.11). NAC had no substantial safety concerns, and it was well tolerated at the doses administered. [1]

COMMENTARY. RYR1-RM is the most frequently diagnosed of all the congenital myopathies, with an estimated US point prevalence of 1:90,000. The RYR1 gene is responsible for calcium channel stability, mutations of which lead to channel hyper- or hyposensitivity and chronic Ca2+ leak. There are no FDA-approved treatments for RYR1-RM. As of 2018, the following were some of the therapeutic approaches postulated for RYR1-RM based on the pathomechanism of disease and potential targets: RyR1 channel stabilization using Rycal ®, chaperones such as Sodium 4-phenylbutyrate, enhancing sarco-endoplasmic reticulum Ca2+ ATPase expression by 5-Aminoimidazole-4-carboxamide ribonucleoside, dantrolene as a RyR1 channel antagonist, carvedilol (a beta-blocker) and an acetylcholinesterase inhibitor such as pyridostigmine. A gene-based approach using adenovirus-mediated therapy was not possible, as the RYR1 gene is 159 kb long and exceeds the ~5 kb packaging capacity [2].

This study used NAC as an approach as it was readily available and had been FDA approved for acetaminophen overdose and other pulmonary conditions. NAC is a precursor to glutathione and is known to reduce oxidative stress. NAC was also shown to have a beneficial effect on muscle function and structure in both zebrafish and mouse models of RYR1-RM.

The following seemed to be some of the reasons that NAC may not have shown benefit in this study: the oral route of NAC administration may have undergone extensive first-pass metabolism and therefore decreased the overall drug availability, the low sample size may not have permitted detection of a clinically meaningful difference, the 6MWT distance was based on Duchenne muscular dystrophy minimum clinically important difference and not on RYR1-RM specifically, and finally the 15-F2t isoprostane levels could have been influenced by diet and exercise and were not corrected for [1].

This was a well-designed and executed study that was based on sound preclinical evidence. This study provides Class I evidence that treatment with oral NAC does not decrease oxidative stress as measured by 15-F2t isoprostane. This study for RYR1-RM will certainly benefit the design for future trials.

Disclosures

The author has declared that no competing interests exist.

References

  1. Todd, JJ Lawal, TA Witherspoon, JW Chrismer, IC Razaqyar, MS Punjabi, M et al. (2020). Randomized controlled trial of Nacetylcysteine therapy for RYR1-related myopathies. Neurology Mar 202094(13): e1434–44. https://doi.org/10.1212/WNL.0000000000008872. [PubMed]  

  2. Lawal, TA, Todd, JJ and Meilleur, KG (2018). Ryanodine Receptor 1-Related Myopathies: Diagnostic and Therapeutic Approaches. Neurotherapeutics Oct 201815(4): 885–899. do: https://doi.org/10.1007/s13311-018-00677-1. 


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