Bertoni C
Department of Neurology and Neurological Sciences, Stanford University Medical Center, Room A-343, Stanford, CA 94305-5235, USA.
Acta Myol. 2005 Dec;24(3):194-201.
In the last decade, outstanding progress has been made in the development of new approaches to treat neuromuscular disorders and in particular Duchenne muscular dystrophy (DMD). The use of oligonucleotides to induce single base pair alterations in the dystrophin gene and restore gene expression in skeletal muscle has proven to be a feasible alternative approach to dystrophin gene replacement. Oligonucleotide-mediated gene editing for dystrophin has the potential to treat the disorder permanently and effectively. Many hurdles however still need to be overcome before this technology can enter into a clinical setting. Understanding the mechanisms of the repair process is a key for the design of oligonucleotides capable to induce gene repair more efficiently and precisely. The future of this technology will depend, ultimately, on the development of safe delivery systems capable to target a large number of muscles. Furthermore, before using oligonucleotides into a clinical setting, we will need to evaluate issues of toxicity, which will have to be balanced with the severity of the disease and the prognosis of the patient. Finally, the rapid progress that has been made to scale up the production of synthetic oligonucleotides will enable the synthesis from micrograms to milligrams quantities allowing this field to move from the bench to the bedside. This review will describe the basic mechanisms of oligonucleotide-mediated gene editing and will explain the potential, hurdles and substantial results obtained using this technology in the treatment of muscular dystrophies.
在过去十年中，治疗神经肌肉疾病，尤其是杜氏肌营养不良症（DMD）的新方法取得了显著进展。使用寡核苷酸诱导肌营养不良蛋白基因中的单碱基对改变并恢复骨骼肌中的基因表达已被证明是肌营养不良蛋白基因替代的一种可行替代方法。寡核苷酸介导的肌营养不良蛋白基因编辑有可能永久有效地治疗该疾病。然而，在这项技术能够进入临床应用之前，仍有许多障碍需要克服。了解修复过程的机制是设计能够更有效、精确地诱导基因修复的寡核苷酸的关键。这项技术的未来最终将取决于能够靶向大量肌肉的安全递送系统的开发。此外，在将寡核苷酸用于临床之前，我们需要评估毒性问题，毒性问题必须与疾病的严重程度和患者的预后相平衡。最后，在扩大合成寡核苷酸生产方面取得的快速进展将使合成量从微克增加到毫克，从而使该领域能够从实验室走向临床。本综述将描述寡核苷酸介导的基因编辑的基本机制，并解释使用该技术治疗肌肉营养不良症所获得的潜力、障碍和重大成果。
