Ruiz Alexis, Noreen Faiza, Meier Hervé, Buczak Katarzyna, Zorzato Francesco, Treves Susan
Neuromuscular Research Group, Departments of Neurology and Biomedicine, Basel University Hospital, Hebelstrasse 20, 4031 Basel, Switzerland.
Genome plasticity group, Department of Biomedicine, University of Basel, Mattenstrasse 28 4058, Basel, Switzerland.
Hum Mol Genet. 2025 Apr 17;34(9):790-805. doi: 10.1093/hmg/ddaf021.
RYR1-related congenital myopathies are rare disorders that severely impair muscle function and the quality of life of patients and their families. To date no pharmacological therapies are available to treat the severe muscle weakness of affected patients. The most severe forms of RYR1-related congenital myopathies are caused by compound heterozygous mutations (nonsense/frameshift in one allele and a missense mutation in the other), leading to reduced RyR1 protein levels and altered biochemical composition of muscles. In this pre-clinical study, we treated a mouse model carrying the RyR1 p.Q1970fsX16 + p.A4329D compound heterozygous pathogenic variants (dHT mice) for 15 weeks with 0.05 mg/kg 5-aza-2'-deoxycytidine, an FDA-approved drug targeting DNA methyltransferases. We evaluated muscle strength, calcium homeostasis and muscle proteome and report that drug treatment improves all investigated parameters in dHT mice. Importantly, the beneficial effects were particularly significant in fast twitch muscles which are the first muscles to be impaired in patients. In conclusion, this study provides proof of concept for the pharmacological treatment of patients with recessive RYR1-related congenital myopathies with the FDA approved 5-aza-2'-deoxycytidine, supporting its use in a phase 1/2 clinical trial.
与兰尼碱受体1（RYR1）相关的先天性肌病是罕见疾病，会严重损害患者及其家人的肌肉功能和生活质量。迄今为止，尚无药物疗法可治疗受影响患者的严重肌肉无力。与RYR1相关的先天性肌病最严重的形式是由复合杂合突变（一个等位基因中的无义/移码突变和另一个等位基因中的错义突变）引起的，导致兰尼碱受体1（RyR1）蛋白水平降低以及肌肉生化组成改变。在这项临床前研究中，我们用0.05毫克/千克的5-氮杂-2'-脱氧胞苷（一种FDA批准的靶向DNA甲基转移酶的药物）对携带RyR1 p.Q1970fsX16 + p.A4329D复合杂合致病变异的小鼠模型（双杂合子小鼠，dHT小鼠）进行了15周的治疗。我们评估了肌肉力量、钙稳态和肌肉蛋白质组，并报告药物治疗改善了dHT小鼠所有研究参数。重要的是，有益效果在快肌中尤为显著，而快肌是患者中最早受损的肌肉。总之，本研究为使用FDA批准的5-氮杂-2'-脱氧胞苷对隐性RYR1相关先天性肌病患者进行药物治疗提供了概念验证，支持其在1/2期临床试验中的应用。
