University of Alberta, Faculty of Medicine and Dentistry, Department of Medical Genetics , Edmonton, Alberta , Canada.
Expert Opin Biol Ther. 2014 Jun;14(6):809-19. doi: 10.1517/14712598.2014.896335. Epub 2014 Mar 12.
Antisense oligonucleotide (AON) therapy is a form of treatment for genetic or infectious diseases using small, synthetic DNA-like molecules called AONs. Recent advances in the development of AONs that show improved stability and increased sequence specificity have led to clinical trials for several neuromuscular diseases. Impressive preclinical and clinical data are published regarding the usage of AONs in exon-skipping and splice modulation strategies to increase dystrophin production in Duchenne muscular dystrophy (DMD) and survival of motor neuron (SMN) production in spinal muscular atrophy (SMA).
In this review, we focus on the current progress and challenges of exon-skipping and splice modulation therapies. In addition, we discuss the recent failure of the Phase III clinical trials of exon 51 skipping (drisapersen) for DMD.
The main approach of AON therapy in DMD and SMA is to rescue ('knock up' or increase) target proteins through exon skipping or exon inclusion; conversely, most conventional antisense drugs are designed to knock down (inhibit) the target. Encouraging preclinical data using this 'knock up' approach are also reported to rescue dysferlinopathies, including limb-girdle muscular dystrophy type 2B, Miyoshi myopathy, distal myopathy with anterior tibial onset and Fukuyama congenital muscular dystrophy.
反义寡核苷酸（AON）疗法是一种使用称为 AON 的小型合成 DNA 样分子治疗遗传或传染病的治疗方法。AON 发展的最新进展显示出稳定性提高和序列特异性增加，已导致几种神经肌肉疾病的临床试验。关于 AON 在外显子跳跃和剪接调节策略中的使用，发表了令人印象深刻的临床前和临床数据，以增加杜氏肌营养不良症（DMD）中的肌营养不良蛋白产生和脊髓性肌萎缩症（SMA）中的运动神经元（SMN）产生的存活率。
在这篇综述中，我们重点介绍外显子跳跃和剪接调节疗法的最新进展和挑战。此外，我们还讨论了 DMD 中exon51 跳跃（drisapersen）的 III 期临床试验最近失败的情况。
AON 疗法在 DMD 和 SMA 中的主要方法是通过外显子跳跃或外显子包含来拯救（“上调”或增加）靶蛋白；相反，大多数常规反义药物旨在下调（抑制）靶标。使用这种“上调”方法的令人鼓舞的临床前数据也被报道可挽救肌营养不良症，包括肢带型肌营养不良症 2B、Miyoshi 肌病、胫骨前起始的远端肌病和 Fukuyama 先天性肌营养不良症。
