Division of Child Neurology, Department of Neurology, Columbia University Medical Center, 180 Fort Washington Ave, New York, NY, 10032, USA.
Paediatr Drugs. 2022 Nov;24(6):585-602. doi: 10.1007/s40272-022-00529-8. Epub 2022 Aug 27.
Spinal muscular atrophy (SMA) is an autosomal recessive degenerative neuromuscular disorder characterized by loss of spinal motor neurons leading to muscle weakness and atrophy that is caused by survival motor neuron (SMN) protein deficiency resulting from the biallelic loss of the SMN1 gene. The SMN2 gene modulates the SMA phenotype, as a small fraction of its transcripts are alternatively spliced to produce full-length SMN (fSMN) protein. SMN-targeted therapies increase SMN protein; mRNA therapies, nusinersen and risdiplam, increase the amount of fSMN transcripts alternatively spliced from the SMN2 gene, while gene transfer therapy, onasemnogene abeparvovec xioi, increases SMN protein by introducing the hSMN gene into various tissues, including spinal cord via an AAV9 vector. These SMN-targeted therapies have been found effective in improving outcomes and are approved for use in SMA in the US and elsewhere. This article discusses the clinical trial results for SMN-directed therapies with a focus on efficacy, side effects and treatment response predictors. It also discusses preliminary data from muscle-targeted trials, as single agents and in combination with SMN-targeted therapies, as well as other classes of SMA treatments.
脊髓性肌萎缩症（SMA）是一种常染色体隐性退行性神经肌肉疾病，其特征是脊髓运动神经元丧失，导致肌肉无力和萎缩，这是由生存运动神经元（SMN）蛋白缺乏引起的，其原因是 SMN1 基因的双等位基因缺失。SMN2 基因调节 SMA 表型，因为其转录本的一小部分被选择性剪接，产生全长 SMN（fSMN）蛋白。SMN 靶向治疗可增加 SMN 蛋白；mRNA 疗法，nusinersen 和 risdiplam，增加了从 SMN2 基因选择性剪接的 fSMN 转录本的数量，而基因转移治疗，onasemnogene abeparvovec xioi，通过将 hSMN 基因引入包括脊髓在内的各种组织，通过 AAV9 载体增加 SMN 蛋白。这些 SMN 靶向治疗已被证明可有效改善预后，并已获得批准在美国和其他地方用于 SMA。本文讨论了 SMN 靶向治疗的临床试验结果，重点是疗效、副作用和治疗反应预测因素。它还讨论了肌肉靶向试验的初步数据，作为单一药物以及与 SMN 靶向治疗联合使用的情况，以及其他 SMA 治疗类别。
