How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy.
How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy.
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DOI：
10.1038/gt.2017.34
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发表时间：
2017-09
期刊：
影响因子：
5.1
通讯作者：
Singh RN
中科院分区：
文献类型：
--
作者：
Singh NN;Howell MD;Androphy EJ;Singh RN
脊髓性肌萎缩症 (SMA) 是一种导致婴儿死亡的重要遗传性疾病，是由于 SMN1 基因缺失或突变导致运动神经元 (SMN) 存活蛋白水平低下所致。 SMN2 是人类中存在的 SMN1 的几乎相同的副本，无法补偿由于前 mRNA 剪接过程中外显子 7 的主要跳跃而导致的 SMN1 损失。随着最近 FDA 批准 nusinersen (Spinraza™)，纠正 SMN2 外显子 7 剪接作为 SMA 疗法的潜力已得到肯定。 Nusinersen 是一种反义寡核苷酸，针对内含子剪接沉默子 N1 (ISS-N1)，于 2004 年在马萨诸塞大学医学院发现。 ISS-N1 已成为使用不同化学物质以及不同 SMA 小鼠模型测试反义寡核苷酸治疗功效的模型靶点。在这里，我们提供了导致 ISS-N1 发现的事件的历史记录，并描述了独立验证的影响，这些独立验证提高了 ISS-N1 作为治疗遗传疾病最有效的反义靶点之一的形象。 nusinersen 最近的批准为刚刚开始发挥其潜力的反义技术提供了急需的推动力。除了治疗 SMA 之外，ISS-N1 靶标还具有完善核酸技术各个方面的巨大潜力，可改善无数的病理状况。
Spinal muscular atrophy (SMA), a prominent genetic disease of infant mortality, is caused by low levels of survival motor neuron (SMN) protein owing to deletions or mutations of the SMN1 gene. SMN2, a nearly identical copy of SMN1 present in humans, cannot compensate for the loss of SMN1 due to predominant skipping of exon 7 during pre-mRNA splicing. With the recent FDA approval of nusinersen (Spinraza™), the potential for correction of SMN2 exon 7 splicing as a SMA therapy has been affirmed. Nusinersen is an antisense oligonucleotide that targets intronic splicing silencer N1 (ISS-N1) discovered in 2004 at the University of Massachusetts Medical School. ISS-N1 has emerged as the model target for testing the therapeutic efficacy of antisense oligonucleotides using different chemistries as well as different mouse models of SMA. Here we provide a historical account of events that led to the discovery of ISS-N1 and describe the impact of independent validations that raised the profile of ISS-N1 as one of the most potent antisense targets for the treatment of a genetic disease. Recent approval of nusinersen provides a much-needed boost for antisense technology that is just beginning to realize its potential. Beyond treating SMA, the ISS-N1 target offers myriad potentials for perfecting various aspects of the nucleic-acid-based technology for the amelioration of the countless number of pathological conditions.
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影响因子：
64.5
作者：
LEFEBVRE, S;BURGLEN, L;MELKI, J
通讯作者：
MELKI, J
影响因子：
--
作者：
Ahmad S;Bhatia K;Kannan A;Gangwani L
通讯作者：
Gangwani L
影响因子：
3.7
作者：
Lin TL;Chen TH;Hsu YY;Cheng YH;Juang BT;Jong YJ
通讯作者：
Jong YJ
脊柱肌肉萎缩儿童的鞘内注射：Nusinersen临床试验经验。
影响因子：
1.9
作者：
Haché M;Swoboda KJ;Sethna N;Farrow-Gillespie A;Khandji A;Xia S;Bishop KM
通讯作者：
Bishop KM
影响因子：
11.2
作者：
Bowerman, Melissa;Swoboda, Kathryn J.;Michalski, John-Paul;Wang, Gen-Sheng;Reeks, Courtney;Beauvais, Ariane;Murphy, Kelley;Woulfe, John;Screaton, Robert A.;Scott, Fraser W.;Kothary, Rashmi
通讯作者：
Kothary, Rashmi