Nicolau Stefan, Malhotra Jyoti, Kaler Maryann, Magistrado-Coxen Pamela, Iammarino Megan A, Reash Natalie F, Frair Emma C, Wijeratne Saranga, Kelly Benjamin J, White Peter, Lowes Linda P, Waldrop Megan A, Flanigan Kevin M
Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH, USA.
Sarepta Therapeutics Inc., Cambridge, MA, USA.
J Neuromuscul Dis. 2024;11(3):679-685. doi: 10.3233/JND-230107.
Single exon duplications account for disease in a minority of Duchenne muscular dystrophy patients. Exon skipping in these patients has the potential to be highly therapeutic through restoration of full-length dystrophin expression. We conducted a 48-week open label study of casimersen and golodirsen in 3 subjects with an exon 45 or 53 duplication. Two subjects (aged 18 and 23 years) were non-ambulatory at baseline. Upper limb, pulmonary, and cardiac function appeared stable in the 2 subjects in whom they could be evaluated. Dystrophin expression increased from 0.94 % ±0.59% (mean±SD) of normal to 5.1% ±2.9% by western blot. Percent dystrophin positive fibers also rose from 14% ±17% at baseline to 50% ±42% . Our results provide initial evidence that the use of exon-skipping drugs may increase dystrophin levels in patients with single-exon duplications.
单外显子重复在少数杜氏肌营养不良患者中导致疾病。在这些患者中，外显子跳跃有可能通过恢复全长抗肌萎缩蛋白表达而具有高度治疗作用。我们对3名患有外显子45或53重复的受试者进行了一项为期48周的卡西莫森和戈洛迪森开放标签研究。两名受试者（年龄分别为18岁和23岁）在基线时不能行走。上肢、肺部和心脏功能在可评估的2名受试者中似乎保持稳定。通过蛋白质印迹法，抗肌萎缩蛋白表达从正常水平的0.94%±0.59%（平均值±标准差）增加到5.1%±2.9%。抗肌萎缩蛋白阳性纤维百分比也从基线时的14%±17%升至50%±42%。我们的结果提供了初步证据，表明使用外显子跳跃药物可能会增加单外显子重复患者的抗肌萎缩蛋白水平。
