Baine Stephen, Wier Chris, Lemmerman Luke, Cooper-Olson Grace, Kempton Amber, Haile Alex, Endres Julian, Fedoce Alessandra, Nesbit Ellyn, Rodino-Klapac Louise R, Potter Rachael A
Sarepta Therapeutics, Inc., Cambridge, Massachusetts, USA.
Hum Gene Ther. 2024 Dec;35(23-24):978-988. doi: 10.1089/hum.2024.013. Epub 2024 Nov 28.
Delandistrogene moxeparvovec is a gene transfer therapy for Duchenne muscular dystrophy (DMD) that uses an adeno-associated viral vector to deliver a micro-dystrophin transgene to skeletal and cardiac muscle. This study evaluated the long-term survival and cardiac efficacy of delandistrogene moxeparvovec in a DMD-mutated (DMD) rat model of DMD-related cardiomyopathy. DMD male rats, aged 21-42 days, were injected with 1.33 × 10 viral genomes/kilogram (vg/kg) delandistrogene moxeparvovec and followed for 12, 24, and 52 weeks. Ambulation was recorded the Photobeam Activity System, whereas echocardiograms, cardiomyocyte contractility, calcium handling, and histological analysis of fibrosis were used to evaluate cardiac disease at 12-, 24-, and 52-weeks post-treatment. A separate cohort of rats was used to assess the impact of delandistrogene moxeparvovec on survival. Treatment with delandistrogene moxeparvovec extended median survival in DMD rats to >25 months versus the 13-month median survival in saline-control-treated DMD rats. Compared with saline control, delandistrogene moxeparvovec therapy elicited statistically significant improvements across cardiac parameters approaching wild-type values with additional benefits in mobility, histopathology, and fibrosis observed. Transgene expression was maintained up to >25 months and micro-dystrophin expression was broadly distributed across skeletal and cardiac muscle. Taken together, these findings demonstrate long-term cardiac efficacy and improved survival following delandistrogene moxeparvovec treatment in DMD rats.
德蓝地昔韦是一种用于杜氏肌营养不良症（DMD）的基因转移疗法，它使用腺相关病毒载体将微肌营养不良蛋白转基因传递到骨骼肌和心肌。本研究评估了德蓝地昔韦在DMD相关心肌病的DMD突变（DMD）大鼠模型中的长期生存情况和心脏疗效。对21至42日龄的DMD雄性大鼠注射1.33×10病毒基因组/千克（vg/kg）的德蓝地昔韦，并随访12、24和52周。使用光梁活动系统记录行走情况，而在治疗后12周、24周和52周，通过超声心动图、心肌细胞收缩性、钙处理以及纤维化的组织学分析来评估心脏疾病。使用另一组大鼠来评估德蓝地昔韦对生存的影响。与生理盐水对照治疗的DMD大鼠13个月的中位生存期相比，德蓝地昔韦治疗将DMD大鼠的中位生存期延长至>25个月。与生理盐水对照相比，德蓝地昔韦治疗在心脏参数方面引起了具有统计学意义的改善，接近野生型值，在运动能力、组织病理学和纤维化方面也观察到了额外的益处。转基因表达维持了>25个月，微肌营养不良蛋白表达广泛分布于骨骼肌和心肌。综上所述，这些发现表明德蓝地昔韦治疗DMD大鼠后具有长期心脏疗效并改善了生存情况。
