Vlodavets D V
Veltischev Clinical Pediatric Research Institute of Pirogov Russian National Research Medical University, Moscow, Russia.
Zh Nevrol Psikhiatr Im S S Korsakova. 2024;124(2):45-57. doi: 10.17116/jnevro202412402145.
Spinal muscular atrophy (SMA) is a devastating disease that is the leading genetic cause of death in infants and young children. It includes a broad spectrum of phenotypes that are classified into clinical groups based on the age of onset and maximum motor function achieved. The most common form of SMA is due to a defect in the survival motor neuron 1 gene () localized to 5q11.2-q13.3. The development of clinical symptoms and disease progression is thought to be due to decreased levels of survival motor neuron (SMN) protein. SMA type 1 results in almost inevitable mortality within the first 2 years of life. The first two drugs approved globally for the treatment of SMA were the antisense oligonucleotide nusinersen (Spinraza), and the gene therapy onasemnogene abeparvovec-xioi (Zolgensma). Both interventions have approval and restrictions on use in different countries around the world. Despite these approved therapies, the medical unmet need in SMA (the majority of patients with SMA are not on a disease-modifying therapy) remains high with therapies in the pipeline to address some of the remaining limitations. The third and more recently approved drug for SMA is risdiplam (Evrysdi), an orally administered, centrally and peripherally distributed small molecule that modulates SMN2 pre-mRNA splicing toward the production of full-length SMN2 mRNA to increase functional SMN protein levels. In Russia the drug risdiplam was approved for use on November 26, 2020 with indications for the treatment of SMA in patients aged 2 months and older, and in 2023 the indications were expanded - use is allowed starting from the birth. Risdiplam is widely distributed into the CNS and peripheral tissues including muscles. Following risdiplam administration, SMN protein levels compared with baseline levels increase between 2- and 6-fold depending on the SMA phenotype treated. The risdiplam clinical development program currently has four ongoing clinical trials assessing its safety and efficacy. Clinical trials included more than 450 patients receiving risdiplam to date, has been well tolerated and no treatment-related safety findings leading to study withdrawal have been observed. Data from real clinical practice - more than 11.000 patients worldwide receive therapy with risdiplam, also confirm the safety and good tolerability of the drug.
脊髓性肌萎缩症（SMA）是一种严重的疾病，是婴幼儿死亡的主要遗传原因。它包括一系列广泛的表型，根据发病年龄和达到的最大运动功能分为不同的临床组。最常见的SMA形式是由于定位于5q11.2-q13.3的生存运动神经元1基因（）存在缺陷。临床症状的出现和疾病进展被认为是由于生存运动神经元（SMN）蛋白水平降低所致。1型SMA几乎会导致患儿在出生后2年内不可避免地死亡。全球首批获批用于治疗SMA的两种药物分别是反义寡核苷酸药物诺西那生钠（Spinraza）和基因疗法药物onasemnogene abeparvovec-xioi（Zolgensma）。这两种干预措施在世界不同国家均已获批，但在使用上也有相应限制。尽管有这些获批疗法，但SMA的医疗需求未满足情况（大多数SMA患者未接受疾病修饰疗法）仍然很高，目前仍有一些在研疗法旨在解决部分剩余的局限性问题。第三种也是最近获批用于治疗SMA的药物是利司扑兰（Evrysdi），这是一种口服的、在中枢和外周均有分布的小分子药物，它可调节SMN2前体mRNA的剪接，促使全长SMN2 mRNA生成，从而提高功能性SMN蛋白水平。在俄罗斯，利司扑兰于2020年11月26日获批使用，适应证为治疗2个月及以上年龄的SMA患者，2023年适应证扩大——允许从出生起使用。利司扑兰广泛分布于中枢神经系统和包括肌肉在内的外周组织。服用利司扑兰后，根据所治疗的SMA表型不同，SMN蛋白水平与基线水平相比会增加2至6倍。利司扑兰的临床开发项目目前有四项正在进行的临床试验，评估其安全性和有效性。截至目前，临床试验已纳入450多名接受利司扑兰治疗的患者，该药耐受性良好，未观察到导致研究中止的与治疗相关的安全问题。来自真实临床实践的数据——全球超过11000名患者接受利司扑兰治疗，也证实了该药的安全性和良好耐受性。
