本文由小咖机器人翻译整理

期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-023-02730-9

摘要内容如下：

肢带型肌营养不良症2E/R4是由β-肌聚糖（SGCB）基因突变引起的，导致SGCB缺乏和随后的肌肉损失。我们开发了一种基于功能性替代缺陷SCB蛋白的基因治疗方法。在此，我们报道了一项首次在人类中进行的、开放标签的、非随机的、1/2期试验的中期结果，该试验评估了Bidridistrogene Xeboparvovec的安全性和有效性，Bidridistrogene Xeboparvovec是一种基于腺相关病毒的基因疗法，含有密码子优化的、全长的人类SGCB转基因。年龄在4-15岁、两个等位基因均证实有SGCB突变的患者接受一次静脉输注1.85×1013载体基因组拷贝KG-1（COHORT1，n=3）或7.41×1013载体基因拷贝KG-1（COHORT2，n=3）。主要终点是安全性，次要终点是从基线到第60天骨骼肌中SGCB表达的变化我们报告了第2年的中期结果（试验正在进行中）。最常见的治疗相关不良事件是呕吐（6名患者中的4名）和γ-谷氨酰转移酶升高（6名患者中的3名）。严重不良事件通过标准治疗得到解决。观察到强大的SGCB表达：第60天平均（S.D.）正常表达百分比在队列1中为36.2%（2.7%），在队列2中为62.1%（8.7%）。事后探索性分析显示，使用北极星评估肢带型肌营养不良症的初步运动改善可维持至第2年。Bidridistrogene Xeboparvovec的2年安全性和有效性支持临床开发进展。需要进一步的研究来证实这种基因疗法的长期安全性和有效性。ClinicalTrials.gov注册：NCT03652259。

英文原文如下：

Abstracts

Limb-girdle muscular dystrophy 2E/R4 is caused by mutations in the β-sarcoglycan (SGCB) gene, leading to SGCB deficiency and consequent muscle loss. We developed a gene therapy approach based on functional replacement of the deficient SCB protein. Here we report interim results from a first-in-human, open-label, nonrandomized, phase 1/2 trial evaluating the safety and efficacy of bidridistrogene xeboparvovec, an adeno-associated virus-based gene therapy containing a codon-optimized, full-length human SGCB transgene. Patients aged 4-15 years with confirmed SGCB mutations at both alleles received one intravenous infusion of either 1.85 × 1013 vector genome copies kg-1 (Cohort 1, n = 3) or 7.41 × 1013 vector gene copies kg-1 (Cohort 2, n = 3). Primary endpoint was safety, and secondary endpoint was change in SGCB expression in skeletal muscle from baseline to Day 60. We report interim Year 2 results (trial ongoing). The most frequent treatment-related adverse events were vomiting (four of six patients) and gamma-glutamyl transferase increase (three of six patients). Serious adverse events resolved with standard therapies. Robust SGCB expression was observed: Day 60 mean (s.d.) percentage of normal expression 36.2% (2.7%) in Cohort 1 and 62.1% (8.7%) in Cohort 2. Post hoc exploratory analysis showed preliminary motor improvements using the North Star Assessment for Limb-girdle Type Muscular Dystrophies maintained through Year 2. The 2-year safety and efficacy of bidridistrogene xeboparvovec support clinical development advancement. Further studies are necessary to confirm the long-term safety and efficacy of this gene therapy. ClinicalTrials.gov registration: NCT03652259 .

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