Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland.
Department of Neurology, Medical University of Warsaw, Banacha 1a, 02-097 Warsaw, Poland.
Neurol Neurochir Pol. 2020;54(1):8-13. doi: 10.5603/PJNNS.a2019.0068. Epub 2020 Jan 10.
Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease with an autosomal recessive trait of inheritance and great variability of its clinical course - from the lethal congenital type (SMA0) to the adult-onset form (SMA4). The disease is associated with a deficiency of SMN protein, which is encoded by two genes SMN1 and SMN2. Clinical symptoms depend on mutations in the SMN1 gene. The number of copies of twin similar SMN2 gene, which produces small amounts of SMN protein, is the main phenotype modifier, which determines the clinical severity of the disease. Until recently, it was considered that spinal cord motoneurons undergo selective loss. Recent studies have shown the role of SMN protein in various cellular processes and the multisystemic character of SMA. The aim of the therapeutic strategies developed so far has been to increase the expression of SMN protein by modifying the splicing of SMN2 gene (intrathecally administered antisense oligonucleotide - nusinersen; orally available small molecules: RG7916 and LMI070 or SMN1 gene replacement therapy (AAV9-SMN). The first SMN2-directed antisense oligonucleotide (nusinersen) has demonstrated in clinical trials high efficiency, and it has now been registered. The best effects were obtained in patients who were introduced to the drug in the pre symptomatic period. Studies on other substances are ongoing. The great advances in SMA therapy and increased understanding of the pathogenesis of the disease raise hopes for changes to the natural history of the disease. Simultaneously, it increases awareness of the need to improve the standard of patient care and early diagnosis (newborn screening). Many questions (e.g. emerging phenotypes, combined therapies, systemic vs. intrathecal administration, long-term consequences, and complications of the therapy) will require further studies and observations.
脊髓性肌萎缩症（SMA）是一种进行性神经退行性疾病，具有常染色体隐性遗传特征，其临床病程变化很大——从致命的先天性类型（SMA0）到成年发病形式（SMA4）。该疾病与 SMN 蛋白的缺乏有关，SMN 蛋白由两个基因 SMN1 和 SMN2 编码。临床症状取决于 SMN1 基因的突变。两个相似的 SMN2 基因的拷贝数，即产生少量 SMN 蛋白的基因，是主要的表型修饰因子，决定了疾病的临床严重程度。直到最近，人们还认为脊髓运动神经元发生选择性丧失。最近的研究表明，SMN 蛋白在各种细胞过程中的作用以及 SMA 的多系统特征。到目前为止，所开发的治疗策略的目的一直是通过修饰 SMN2 基因的剪接来增加 SMN 蛋白的表达（鞘内给予反义寡核苷酸- nusinersen；口服小分子：RG7916 和 LMI070 或 SMN1 基因替代疗法（AAV9-SMN）。首个针对 SMN2 的反义寡核苷酸（nusinersen）在临床试验中显示出了高效性，现已注册。在引入药物的前症状期患者中获得了最佳效果。其他物质的研究仍在进行中。SMA 治疗的巨大进步和对疾病发病机制的深入理解，使人们对改变疾病的自然病程抱有希望。同时，它也提高了人们对改善患者护理标准和早期诊断（新生儿筛查）的认识。许多问题（例如新兴表型、联合疗法、全身与鞘内给药、长期后果以及治疗的并发症）都需要进一步的研究和观察。
