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首页> 外文期刊>Clinical drug investigation >Nusinersen: The First Option Beyond Supportive Care for Spinal Muscular Atrophy
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Nusinersen: The First Option Beyond Supportive Care for Spinal Muscular Atrophy

机译：NUSINERSEN：超出支持性护理的第一个选择脊髓肌萎缩

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摘要

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration of spinal motor neurons and poses significant adverse outcome in affected population. Survival motor neuron 1 (SMN1) protein encoded by SMN1 gene located on 5q(13) is critical for survival and functioning of motor neurons. Almost identical gene SMN2, present on the same chromosome, produces a small truncated protein (SMN2) because of skipping of exon 7 from translation due to translation silent C6U substitution in exon 7 of SMN2 pre-mRNA transcript. Only 10% of the SMN2 mRNAs produce full length SMN2 protein by including exon 7 in healthy individuals. A large deletion or sometimes a point mutation in SMN1 gene is responsible for SMA. In this case the number of copies of SMN2 genes in an individual determines the severity of disease (the more the number of copies the less severe the disease). Nusinersen (ISIS 396443) binds to intron splicing silencer-N1 (ISS-N1; a site present ten nucleotides down to the junction of exon 7 and intron 7), modulating the splicing of SMN2 pre-mRNA transcript to increase the inclusion of exon 7, thereby increasing the production of full length SMN2 protein. Major evidence of its efficacy came from a sham controlled phase 3 clinical study ENDEAR. The study was stopped early based on significantly favorable results in interim analysis and all the patients were transitioned to receive nusinersen in an ongoing open-label, phase 3 study, SHINE, which will evaluate the long-term efficacy, safety and tolerability of the drug. Nusinersen is globally the first drug approved (by the US FDA) for treatment of SMA in children and adults.
机译：脊柱肌肉萎缩（SMA）是一种常染色体隐性神经肌病，其特征，其特征在于脊柱运动神经元的变性，并在受影响人群中造成显着的不利结果。 SMN1基因位于5Q（13）的SMN1基因编码的存活电动机神经元1（SMN1）蛋白对运动神经元的存活和运作至关重要。几乎相同的基因SMN2，存在于同一染色体上，产生小截短的蛋白质（SMN2），因为由于SMN2前MRNA转录物的外显子7中的翻译沉默C6U取代而从翻译中跳过外显子7。只有10％的SMN2 mRNA通过在健康个体中包括外显子7，产生全长SMN2蛋白。大缺失或有时SMN1基因的点突变对SMA负责。在这种情况下，个体中SMN2基因的拷贝数决定了疾病的严重程度（拷贝的数量越多，疾病的严重较小）。 Nusinersen（ISIS 396443）与内含子剪接Silencer-N1（ISS-N1;一个位点向外呈现10个核苷酸，下降到外显子7和内含子7），调节SMN2前mRNA转录物的剪接以增加外显子7 ，从而增加全长SMN2蛋白的产生。其疗效的主要证据来自假的受控第3期临床研究。本研究早期停止，基于临时分析的显着有利的结果，所有患者在持续的开放标签，第3阶段研究，闪耀中，所有患者都会过渡以获得植物，这将评估药物的长期疗效，安全性和耐受性。 Nusinersen是全球批准的第一药（由美国FDA）用于治疗儿童和成人的SMA。

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