Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio, USA.
Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA.
Muscle Nerve. 2024 Jan;69(1):93-98. doi: 10.1002/mus.27955. Epub 2023 Aug 14.
INTRODUCTION/AIMS: Delandistrogene moxeparvovec is indicated in the United States for the treatment of ambulatory pediatric patients aged 4 through 5 years with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene. Long-term delandistrogene moxeparvovec microdystrophin protein (a shortened dystrophin that retains key functional domains of the wild-type protein) expression may positively alter disease progression in patients with DMD. We evaluated long-term safety and functional outcomes of delandistrogene moxeparvovec in patients with DMD.
An open-label, phase 1/2a, nonrandomized controlled trial (Study 101; NCT03375164) enrolled ambulatory males, ≥4 to <8 years old, with DMD. Patients received a single intravenous infusion (2.0 × 10 vg/kg by supercoiled quantitative polymerase chain reaction) of delandistrogene moxeparvovec and prednisone (1 mg/kg/day) 1 day before to 30 days after treatment. The primary endpoint was safety. Functional outcomes were change from baseline in North Star Ambulatory Assessment (NSAA) and timed function tests.
Four patients (mean age, 5.1 years) were enrolled. There were 18 treatment-related adverse events; all occurred within 70 days posttreatment and resolved. Mean NSAA total score increased from 20.5 to 27.5, baseline to year 4, with a mean (standard deviation) change of +7.0 (2.9). Post hoc analysis demonstrated a statistically significant and clinically meaningful 9-point difference in NSAA score, relative to a propensity-score-weighted external control cohort (least-squares mean [standard error] = 9.4 [3.4]; P = .0125).
Gene transfer therapy with delandistrogene moxeparvovec treatment is well tolerated, with a favorable safety profile. Functional improvements are sustained through 4 years, suggesting delandistrogene moxeparvovec may positively alter disease progression.
介绍/目的：Delandistrogene moxeparvovec 在美国被批准用于治疗年龄在 4 至 5 岁的、患有杜氏肌营养不良症（DMD）的、经确认携带 DMD 基因突变的、可走动的儿科患者。长期表达 Delandistrogene moxeparvovec 微肌营养不良蛋白（一种缩短的肌营养不良蛋白，保留了野生型蛋白的关键功能域）可能会对 DMD 患者的疾病进展产生积极影响。我们评估了 Delandistrogene moxeparvovec 治疗 DMD 患者的长期安全性和功能结果。
一项开放标签、1/2a 期、非随机对照试验（研究 101；NCT03375164）招募了年龄在 4 至<8 岁之间、可走动的男性 DMD 患者。患者接受单次静脉输注（2.0×10 vg/kg 通过超螺旋定量聚合酶链反应） Delandistrogene moxeparvovec 和泼尼松（1mg/kg/天），在治疗前 1 天至治疗后 30 天。主要终点是安全性。功能结果是从基线到北星门诊评估（NSAA）和计时功能测试的变化。
4 名患者（平均年龄 5.1 岁）入组。共有 18 例与治疗相关的不良事件；所有事件均发生在治疗后 70 天内，并已解决。平均 NSAA 总分从 20.5 增加到 27.5，从基线到第 4 年，平均（标准差）变化为+7.0（2.9）。事后分析显示，与倾向评分加权外部对照队列相比，NSAA 评分有统计学意义和临床意义的 9 分差异（最小二乘均值[标准误差]=9.4[3.4]；P=0.0125）。
Delandistrogene moxeparvovec 基因转移治疗具有良好的耐受性，安全性良好。功能改善可持续 4 年，表明 Delandistrogene moxeparvovec 可能会对疾病进展产生积极影响。
