■强直性肌营养不良1型(DM1)是由DMPK基因中的CTG重复扩增引起的破坏性多系统疾病,随后触发有毒RNA表达和剪接失调。在一项临床前研究中,我们证明了红霉素可以降低DM1模型小鼠异常RNA的毒性并改善异常剪接和运动表型。
■这个多中心,随机化,双盲,安慰剂对照,在日本的三个中心进行了2期试验,目的是通过评估红霉素的安全性和有效性,将临床前发现转化为DM1患者的实际应用.在2019年11月29日至2022年1月20日之间,共招募了30名DM1成年患者,并以1:2:2的比例随机分配,以2日剂量(500mg或800mg)接受安慰剂或红霉素治疗24周。主要结果包括红霉素的安全性和耐受性。次要功效测量包括剪接生物标志物,6分钟步行测试结果,肌肉力量,和血清肌酐激酶(CK)值。该试验在日本临床试验注册中心注册,jRCT2051190069.
■治疗相关的胃肠道症状在红霉素组中更常见,但所有不良事件均为轻度至中度,可自行缓解.没有发现严重的安全问题。与安慰剂组相比,整个红霉素组从基线到第24周的CK水平下降(-6.4U/L[SD149]对182.8[SD228]的平均变化),尽管这种差异没有统计学意义(p=0.070)。对于11种剪接生物标志物中的两种,观察到与安慰剂相比的总体红霉素治疗组中的统计学显著改善,每种生物标志物在试验样品的一半中进行了评估。这些是MBNL1(p=0.048)和CACNA1S(p=0.042)。
■红霉素在DM1患者中表现出良好的安全性和耐受性。需要一个强大的3期试验来评估疗效,基于这项研究的初步发现。
■日本医学研究与发展机构。
UNASSIGNED: Myotonic dystrophy type 1 (DM1) is a devastating multisystemic disorder caused by a CTG repeat expansion in the DMPK gene, which subsequently triggers toxic RNA expression and dysregulated splicing. In a preclinical study, we demonstrated that erythromycin reduces the toxicity of abnormal RNA and ameliorates the aberrant splicing and motor phenotype in DM1 model mice.
UNASSIGNED: This multicentre, randomised, double-blind, placebo-controlled, phase 2 trial was conducted at three centres in Japan to translate preclinical findings into practical applications in patients with DM1 by evaluating the safety and efficacy of erythromycin. Between Nov 29, 2019, and Jan 20, 2022, a total of 30 adult patients with DM1 were enrolled and randomly assigned in a 1:2:2 ratio to receive either placebo or erythromycin at two daily doses (500 mg or 800 mg) for 24 weeks. The primary outcome included the safety and tolerability of erythromycin. The secondary efficacy measures included splicing biomarkers, 6-min walk test results, muscle strength, and serum creatinine kinase (CK) values. This trial is registered with the Japan Registry of Clinical Trials, jRCT2051190069.
UNASSIGNED: Treatment-related gastrointestinal symptoms occurred more frequently in the erythromycin group, but all adverse events were mild to moderate and resolved spontaneously. No serious safety concerns were identified. The CK levels from baseline to week 24 decreased in the overall erythromycin group compared with the placebo group (mean change of -6.4 U/L [SD 149] vs +182.8 [SD 228]), although this difference was not statistically significant (p = 0.070). Statistically significant improvements in the overall erythromycin treated groups compared to placebo were seen for two of the eleven splicing biomarkers that were each evaluated in half of the trial sample. These were MBNL1 (p = 0.048) and CACNA1S (p = 0.042).
UNASSIGNED: Erythromycin demonstrated favourable safety and tolerability profiles in patients with DM1. A well-powered phase 3 trial is needed to evaluate efficacy, building on the preliminary findings from this study.
UNASSIGNED: Japan Agency for Medical Research and Development.