Abstract：
Spinal muscular atrophy (SMA), the most common genetic cause of infantile death, is caused by a mutation in the survival of motor neuron 1 gene (SMN1), leading to the death of motor neurons and progressive muscle weakness. SMN1 normally produces an essential protein called SMN. Although humans possess a paralogous gene called SMN2, ∼90% of the SMN it produces is non-functional. This is due to a mutation in SMN2 that causes the skipping of a required exon during splicing of the pre-mRNA. The first treatment for SMA, nusinersen (brand name Spinraza), was approved by the FDA in 2016 and by the EMU in 2017. Nusinersen is an antisense oligonucleotide-based therapy that alters the splicing of SMN2 to make functional full-length SMN protein. Despite the recent advancements in antisense oligonucleotide therapy and SMA treatment development, nusinersen is faced with a multitude of challenges, such as intracellular and systemic delivery. In recent years, the use of peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) in antisense therapy has gained interest. These are antisense oligonucleotides conjugated to cell-penetrating peptides such as Pips and DG9, and they have the potential to address the challenges associated with delivery. This review focuses on the historic milestones, development, current challenges, and future perspectives of antisense therapy for SMA.
摘要：
脊髓性肌萎缩症(SMA),婴儿死亡最常见的遗传原因，是由运动神经元1基因（SMN1）的存活突变引起的，导致运动神经元死亡和进行性肌肉无力。SMN1通常产生一种称为SMN的必需蛋白质。尽管人类拥有称为SMN2的同源基因，但它产生的SMN中有90％是非功能性的。这是由于SMN2中的突变导致前mRNA剪接期间所需外显子的跳跃。SMA的第一次治疗，nusinersen（品牌名称Spinraza），2016年获得FDA批准，2017年获得EMU批准。Nusinersen是一种基于反义寡核苷酸的疗法，可改变SMN2的剪接以产生功能性全长SMN蛋白。尽管在反义寡核苷酸治疗和SMA治疗发展的最新进展，Nusinersen面临着众多挑战，如细胞内和全身递送。近年来,在反义治疗中使用肽缀合的磷酸二酰胺吗啉代寡聚物(PPMO)已经引起了人们的兴趣.这些是与细胞穿透肽(如Pips和DG9)缀合的反义寡核苷酸,并且它们具有解决与递送相关的挑战的潜力。这次审查的重点是历史性的里程碑，发展,当前的挑战,以及SMA反义治疗的未来前景。
