PDF(Pubmed)
Abstract：
Duchenne muscular dystrophy (DMD) is a systemic progressive muscular disease caused by frame-disrupting mutations in the DMD gene. Although exon-skipping antisense oligonucleotides (AOs) are clinically approved and can correct DMD, insufficient muscle delivery limits efficacy. If AO activity can be enhanced by safe dietary supplements, clinical trials for efficacy can be undertaken rapidly to benefit patients. We showed previously that intravenous glycine enhanced phosphorodiamidate morpholino oligomer (PMO) delivery to peripheral muscles in mdx mice. Here, we demonstrate that the combination of oral glycine and metformin with intravenous PMO enhances PMO activity, dystrophin restoration, extends lifespan, and improves body-wide function and phenotypic rescue of dystrophin /utrophin double knock-out (DKO) mice without any overt adverse effects. The DKO mice treated with the combination without altering the approved administration protocol of PMO show improved cardio-respiratory and behavioral functions. Metformin and glycine individually are ineffective in DMD patients, but the combination of PMO with clinically-approved oral glycine and metformin might improve the efficacy of the treatment also in DMD patients. Our data suggest that this combination therapy might be an attractive therapy for DMD and potentially other muscle diseases requiring systemic treatment with AOs.
摘要：
杜氏肌营养不良症（DMD）是一种由DMD基因中的框架破坏突变引起的系统性进行性肌肉疾病。尽管外显子跳跃反义寡核苷酸（AOs）已获得临床批准，并且可以纠正DMD，肌肉输送不足限制了疗效。如果AO活性可以通过安全的膳食补充剂来增强，疗效临床试验可以迅速进行，以使患者受益。我们先前表明，静脉注射甘氨酸可增强mdx小鼠向外周肌肉的磷酸二酰胺吗啉代寡聚物（PMO）的递送。这里,我们证明，口服甘氨酸和二甲双胍与静脉PMO的组合可增强PMO活性，肌营养不良蛋白恢复，延长寿命，并改善肌养蛋白/utrophin双敲除（DKO）小鼠的全身功能和表型挽救，而没有任何明显的不良反应。在不改变批准的PMO给药方案的情况下用该组合治疗的DKO小鼠显示出改善的心肺功能和行为功能。二甲双胍和甘氨酸单独在DMD患者中无效，但是PMO与临床批准的口服甘氨酸和二甲双胍的组合也可能提高DMD患者的治疗效果.我们的数据表明，这种联合疗法可能是DMD和可能需要AOs全身治疗的其他肌肉疾病的有吸引力的疗法。
