Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands .
Nucleic Acid Ther. 2013 Jun;23(3):228-37. doi: 10.1089/nat.2012.0398. Epub 2013 May 2.
Antisense-mediated exon skipping is a promising therapeutic approach for Duchenne muscular dystrophy. It aims to restore the dystrophin open reading frame by skipping exons with antisense oligonucleotides (AONs) to allow production of partly functional proteins. The approach is currently tested in phase 3 clinical trials, but dosing and maintenance regimens have not yet been well studied. This study compared pharmacokinetic and pharmacodynamic effects of different 2'-O-methyl phosphorothioate RNA AON dosing and maintenance regimens in the preclinical mdx mouse model. When comparing different dosing regimens over a period of 8 weeks, higher levels of AON, exon skipping, and protein were observed in muscle after low daily doses compared with large weekly doses. Secondly, after receiving a high loading dose (1,250 mg/kg) in the first week, mice treated with maintenance injections twice weekly for 8 weeks showed higher preservation of therapeutic effects than mice receiving less or no maintenance injections. In both cases, the regimen resulting in the highest AON and exon skipping levels in muscle also resulted in high AON levels in liver and kidneys. These studies underline the importance of balancing optimal AON efficacy and tolerable levels in non-target organs, which may be fine-tuned by further optimization of AON treatment regimens.
反义寡核苷酸介导的外显子跳跃是治疗杜氏肌营养不良症的一种很有前途的方法。它旨在通过反义寡核苷酸（AON）跳过外显子来恢复肌营养不良蛋白开放阅读框，从而产生部分功能蛋白。该方法目前正在进行 3 期临床试验，但尚未对剂量和维持方案进行充分研究。本研究比较了不同 2'-O-甲基硫代磷酸酯 RNA AON 剂量和维持方案在临床前 mdx 小鼠模型中的药代动力学和药效学效应。当在 8 周的时间内比较不同的剂量方案时，与大剂量每周相比，低剂量每日给药后肌肉中的 AON、外显子跳跃和蛋白水平更高。其次，在第一周接受高负荷剂量（1,250mg/kg）后，接受每周两次维持注射 8 周的小鼠比接受较少或不接受维持注射的小鼠显示出更高的治疗效果维持。在这两种情况下，在肌肉中产生最高 AON 和外显子跳跃水平的方案也导致肝脏和肾脏中的 AON 水平升高。这些研究强调了平衡最佳 AON 疗效和非靶器官可耐受水平的重要性，这可能通过进一步优化 AON 治疗方案来微调。
