Schneider Anne-Fleur E, Aartsma-Rus Annemieke
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Expert Opin Biol Ther. 2021 Mar;21(3):343-359. doi: 10.1080/14712598.2021.1832462. Epub 2020 Oct 19.
Exon skipping compounds restoring the dystrophin transcript reading frame have received regulatory approval for Duchenne muscular dystrophy (DMD). Recently, focus shifted to developing compounds to skip additional exons, improving delivery to skeletal muscle, and to genome editing, to restore the reading frame on DNA level.
We outline developments for reading frame restoring approaches, challenges of mutation specificity, and optimizing delivery. Also, we highlight ongoing efforts to better detect exon skipping therapeutic effects in clinical trials. Searches on relevant terms were performed, focusing on recent publications (<3 years).
Currently, 3 AONS are approved. Whether dystrophin levels are sufficient to slowdown disease progression needs to be confirmed. Enhancing AON uptake by muscles is currently under investigation. Gene editing is an alternative, but one that involves practical and ethical concerns. Given the field's momentum, we believe the efficiency of frame-restoring approaches will improve.
恢复抗肌萎缩蛋白转录本阅读框的外显子跳跃化合物已获得杜氏肌营养不良症（DMD）的监管批准。最近，重点转向开发能跳过更多外显子的化合物，改善向骨骼肌的递送，以及转向基因组编辑，以在DNA水平恢复阅读框。
我们概述了阅读框恢复方法的进展、突变特异性的挑战以及递送优化。此外，我们强调了在临床试验中更好地检测外显子跳跃治疗效果的持续努力。针对相关术语进行了检索，重点关注近期（<3年）的出版物。
目前，有3种反义寡核苷酸（AON）已获批准。抗肌萎缩蛋白水平是否足以减缓疾病进展尚需确认。目前正在研究增强肌肉对AON的摄取。基因编辑是一种替代方法，但涉及实际和伦理问题。鉴于该领域的发展势头，我们相信阅读框恢复方法的效率将会提高。
