PRECISION MEDICINE FOR RYR1-RELATED MYOPATHIES: A COMPREHENSIVE REVIEW OF GENE EDITING, PHARMACOLOGICAL INTERVENTIONS, AND SOCIETAL IMPLICATIONS
Abstract
Ryanodine receptor 1-related myopathies (RYR1-RM) constitute the most prevalent class of non-dystrophic congenital myopathies, representing a complex intersection of genetic heterogeneity, molecular pathology, and evolving therapeutic paradigms. Characterized by mutations in the RYR1 gene, these disorders manifest across a broad clinical spectrum ranging from static congenital weakness to life-threatening pharmacogenetic traits such as Malignant Hyperthermia Susceptibility (MHS). This review article provides an exhaustive synthesis of the scientific and societal landscape of RYR1-RM as of 2025. We provide a deep mechanistic analysis of the RyR1 channel's structure-function relationship, elucidated through recent cryo-electron microscopy breakthroughs that define the "leaky channel" pathophysiology. We critically evaluate the emerging pharmacological arsenal, including the landmark Phase 1b trial of the Rycal compound ARM210 (S48168), the novel application of epigenetic modulation via 5-aza-2'-deoxycytidine, and the repurposed utility of dantrolene and salbutamol. Furthermore, we dissect the frontier of precision genetic engineering, detailing the mechanics and efficacy of Prime Editing and Twin Prime Editing strategies, alongside the development of myotropic viral vectors (MyoAAV) designed to overcome the delivery barriers inherent to the massive RYR1 gene. Beyond the bench, this report integrates a rigorous social science perspective, analyzing the health economic frameworks (ICER, QALYs) that govern access to orphan drugs, the ethical dimensions of somatic gene editing for non-lethal disabilities, and the transformative role of patient advocacy in the rare disease ecosystem. This multidimensional review aims to serve as a foundational resource for clinicians, researchers, and policymakers navigating the complex transition from supportive care to disease-modifying precision medicine.
References
Amburgey, K., Bailey, A., Hwang, J. H., Tarnopolsky, M. A., Bonnemann, C. G., Medne, L.,... & Dowling, J. J. (2013). Genotype–phenotype correlations in recessive RYR1-related myopathies. Orphanet Journal of Rare Diseases, 8(1), 117. https://doi.org/10.1186/1750-1172-8-117
Andersson, D. C., Betzenhauser, M. J., Reiken, S., Meli, A. C., Umanskaya, A., Xie, W.,... & Marks, A. R. (2011). Ryanodine receptor oxidation causes intracellular calcium leak and muscle weakness in aging. Cell Metabolism, 14(2), 196–207. https://doi.org/10.1016/j.cmet.2011.05.014
Anzalone, A. V., Gao, X. D., Podracky, C. J., Nelson, A. T., Koblan, L. W., Raguram, A.,... & Liu, D. R. (2022). Programmable deletion, replacement, integration and inversion of large DNA sequences with twin prime editing. Nature Biotechnology, 40(5), 731–740. https://doi.org/10.1038/s41587-021-01133-w
Anzalone, A. V., Randolph, P. B., Davis, J. R., Sousa, A. A., Koblan, L. W., Levy, J. M.,... & Liu, D. R. (2019). Search-and-replace genome editing without double-strand breaks or donor DNA. Nature, 576(7785), 149–157. https://doi.org/10.1038/s41586-019-1711-4
Durham, W. J., Aracena-Parks, P., Long, C., Rossi, A. E., Goonasekera, S. A., Boncompagni, S.,... & Dirksen, R. T. (2008). RyR1 S-nitrosylation underlies environmental heat stroke and sudden death in Y522S RyR1 knock-in mice. Cell, 133(1), 53–65. https://doi.org/10.1016/j.cell.2008.02.042
Godbout, K., Dugas, M., Ramezani, S., Falle, A., Lamothe, G., Canet, G.,... & Tremblay, J. P. (2025). Universal Prime Editing Therapeutic Strategy for RyR1-Related Myopathies: A Protective Mutation Rescues Leaky RyR1 Channel. International Journal of Molecular Sciences, 26(7), 2835. https://doi.org/10.3390/ijms26072835
Godbout, K., Rousseau, J., & Tremblay, J. P. (2024). Successful Correction by Prime Editing of a Mutation in the RYR1 Gene Responsible for a Myopathy. Cells, 13(1), 31. https://doi.org/10.3390/cells13010031
Hedermann, G., Vissing, C. R., Heje, K., Preisler, N., Witting, N., & Vissing, J. (2016). Aerobic training in patients with congenital myopathy. PLoS One, 11(1), e0146036. https://doi.org/10.1371/journal.pone.0146036
Ibarra Moreno, C. A., Kraeva, N., Zvaritch, E., Jungbluth, H., Voermans, N. C., & Riazi, S. (2023). Oral Dantrolene for Myopathic Symptoms in Malignant Hyperthermia–Susceptible Patients: A 25-Year Retrospective Cohort Study of Adverse Effects and Tolerability. Anesthesia & Analgesia, 136(3), 569–577. https://doi.org/10.1213/ANE.0000000000006207
Ibarra Moreno, C. A., Kraeva, N., Zvaritch, E., & Riazi, S. (2024). Myopathic manifestations across the adult lifespan of malignant-hyperthermia-susceptible patients: a narrative review. British Journal of Anaesthesia, 133(4), 759–767. https://doi.org/10.1016/j.bja.2024.05.046
Institute for Clinical and Economic Review. (2019). Deflazacort, Eteplirsen, and Golodirsen for Duchenne Muscular Dystrophy: Effectiveness and Value. https://icer.org/assessment/duchenne-muscular-dystrophy-2019/
Jungbluth, H., Dowling, J. J., Ferreiro, A., & Muntoni, F. (2018). 217th ENMC International Workshop: RYR1-related myopathies, Naarden, The Netherlands, 29–31 January 2016. Neuromuscular Disorders, 28(1), 26–37. https://doi.org/10.1016/j.nmd.2016.06.001
Kuo, A., Todd, J. J., Witherspoon, J. W., Cohen, J. S., Bönnemann, C. G., & Dowling, J. J. (2019). Reliability and validity of fatigue questionnaires in RYR1-related disorders. Journal of Neuromuscular Diseases, 6(1), 133–141. https://doi.org/10.3233/jnd-180335
Lanner, J. T., Georgiou, D. K., Dagnino-Acosta, A., Ainbinder, A., Cheng, Q., Joesch-Cohen, L.,... & Hamilton, S. L. (2012). AICAR prevents heat-induced sudden death in RyR1 mutant mice independent of AMPK activation. Nature Medicine, 18(2), 244–251. https://doi.org/10.1038/nm.2598
Larkindale, J., Yang, W., Hogan, P. F., Simon, C. J., Zhang, Y., Jain, A.,... & McDonald, C. M. (2014). Cost of illness for neuromuscular diseases in the United States. Muscle & Nerve, 49(3), 431–438. https://doi.org/10.1002/mus.23942
Lawal, T. A., Wires, E. S., Terry, N. L., Dowling, J. J., & Todd, J. J. (2020). Preclinical model systems of ryanodine receptor 1-related myopathies and malignant hyperthermia: a comprehensive scoping review of works published 1990-2019. Orphanet Journal of Rare Diseases, 15(1), 113. https://doi.org/10.1186/s13023-020-01384-x
Maggi, L., Scoto, M., Cirak, S., Robb, S. A., Klein, A., Lillis, S.,... & Muntoni, F. (2013). Congenital myopathies - clinical features and frequency of individual subtypes diagnosed over a 5-year period in the United Kingdom. Neuromuscular Disorders, 23(3), 195–205. https://doi.org/10.1016/j.nmd.2013.01.004
Marks, A. R. (2013). Calcium cycling proteins and heart failure: mechanisms and therapeutics. The Journal of Clinical Investigation, 123(1), 46–52. https://doi.org/10.1172/jci62834
McKie, A. B., Al-Windy, N. Y., Morten, K. J., Matthews, E., Sharp, L. J., & Jungbluth, H. (2014). Germline mutations in RYR1 are associated with foetal akinesia deformation sequence/lethal multiple pterygium syndrome. Acta Neuropathologica Communications, 2, 148. https://doi.org/10.1186/s40478-014-0148-0
Messina, S., Hartley, L., Main, M., Kinali, M., & Muntoni, F. (2004). Pilot trial of salbutamol in central-core and multi-minicore disease. Neuropediatrics, 35(5), 262–266. https://doi.org/10.1055/s-2004-821173
Michelucci, A., De Marco, A., Guarnier, F. A., Protasi, F., & Boncompagni, S. (2017). Antioxidant treatment reduces formation of structural cores and improves muscle function in RYR1Y522S/WT mice. Oxidative Medicine and Cellular Longevity, 2017, 6792694. https://doi.org/10.1155/2017/6792694
National Academies of Sciences, Engineering, and Medicine. (2017). Human Genome Editing: Science, Ethics, and Governance. The National Academies Press. https://doi.org/10.17226/24623
O’Connor, T. N., Lamont, P. J., Finlayson, S., Jungbluth, H., & Voermans, N. C. (2023). RYR1-related diseases workshop: from mechanisms to treatments. Journal of Neuromuscular Diseases, 10(1), 135–154. https://doi.org/10.3233/JND-221609
Ruiz, A., Noreen, F., Meier, H., & Treves, S. (2025). 5-aza-2'-deoxycytidine improves skeletal muscle function in a mouse model for recessive RYR1-related congenital myopathy. Human Molecular Genetics. Advance online publication. https://doi.org/10.1093/hmg/ddaf021
Sarkozy, A., Sa, M., Ridout, D., & Muntoni, F. (2023). Long-term natural history of paediatric dominant and recessive RYR1-related myopathy. Neurology, 101(15), e1495-e1508. https://doi.org/10.1212/wnl.0000000000207723
Tabebordbar, M., Lagerborg, K. A., Stanton, A., King, E. M., Ye, S., Tellez, L.,... & Sabeti, P. C. (2021). Directed evolution of a family of AAV capsid variants enabling potent muscle-directed gene delivery across species. Cell, 184(19), 4919–4938. https://doi.org/10.1016/j.cell.2021.08.028
Todd, J. J., Lawal, T. A., Chrismer, I. C., Witherspoon, J. W., & Mohassel, P. (2024). Rycal S48168 (ARM210) for RYR1-related myopathies: phase-one open-label trial. EClinicalMedicine, 68, 102433. https://doi.org/10.1016/j.eclinm.2024.102433
Todd, J. J., Lawal, T. A., Witherspoon, J. W., Wu, T., Vatsayan, A., & Bönnemann, C. G. (2020). Randomized controlled trial of N-acetyl-cysteine therapy for RYR1-related myopathies. Neurology, 94(13), e1434–e1444. https://doi.org/10.1212/wnl.0000000000008872
Todd, J. J., Sagar, V., Lawal, T. A., Allen, C., Razaqyar, M. S., & Dowling, J. J. (2018). Correlation of phenotype with genotype and protein structure in RYR1-related disorders. Journal of Neurology, 265(11), 2506–2524. https://doi.org/10.1007/s00415-018-9033-2
Van Petegem, F. (2012). Ryanodine receptors: structure and function. Journal of Biological Chemistry, 287(38), 31624–31632. https://doi.org/10.1074/jbc.r112.349068
Voermans, N. C., Custers, J. A. E., Verhaak, C., & van Engelen, B. G. M. (2019). Functional impairments, fatigue and quality of life in RYR1-related myopathies. Neuromuscular Disorders, 29(1), 30–38. https://doi.org/10.1016/j.nmd.2018.10.006
Voermans, N. C., Snoeck, M., & Jungbluth, H. (2016). RYR1-related rhabdomyolysis: A common but probably underdiagnosed manifestation of skeletal muscle Ryanodine receptor dysfunction. Revue Neurologique, 172(10), 546–558. https://doi.org/10.1016/j.neurol.2016.07.018
Yan, Z., Bai, X. C., Yan, C., Wu, J., Li, Z., Xie, T.,... & Scheres, S. H. (2015). Structure of the rabbit ryanodine receptor RyR1 at near-atomic resolution. Nature, 517(7532), 50–55. https://doi.org/10.1038/nature14063
Zhou, H., Yamaguchi, N., Xu, L., Wang, Y., Sewry, C., Jungbluth, H.,... & Meissner, G. (2007). Characterization of recessive RYR1 mutations in core myopathies. Human Molecular Genetics, 15(18), 2791–2803. https://doi.org/10.1093/hmg/ddl221
Copyright (c) 2026 Magdalena Fidelis, Maria Wojcieszek, Katarzyna Gondek, Dominika Gacka, Agnieszka Zalewska, Aleksandra Mączyńska, Noor Alhuda Al-karawi, Paulina Kędziorek, Zuzanna Tanç
This work is licensed under a Creative Commons Attribution 4.0 International License.
All articles are published in open-access and licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). Hence, authors retain copyright to the content of the articles.
CC BY 4.0 License allows content to be copied, adapted, displayed, distributed, re-published or otherwise re-used for any purpose including for adaptation and commercial use provided the content is attributed.
