Division of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
West China School of Medicine, West China Hospital, Sichuan University, Chengdu, China.
Hum Gene Ther. 2023 Mar;34(5-6):180-191. doi: 10.1089/hum.2022.189.
Spinal muscular atrophy (SMA) is a recessive, neurodegenerative disorder. It is one of the most common genetic causes of infant mortality and is characterized by muscle weakness, loss of ambulation, and respiratory failure. SMA is primarily caused by a homozygous deletion or mutation of the survival motor neuron 1 (SMN1) gene. Humans possess a second, nearly identical copy of SMN, known as the SMN2 gene. Although the disease severity correlates inversely with the number of SMN2 copies present, it can never completely compensate for the loss of SMN1 in patients with SMA; SMN2 expresses only a fraction of the functional SMN transcript. The SMN protein is ubiquitous in human cells and plays several roles, ranging from assembling the spliceosome machinery to autophagy, RNA metabolism, signal transduction, cellular homeostasis, DNA repair, and recombination. Although the underlying mechanism remains unclear, anterior horn cells of the spinal cord gray matter are highly vulnerable to decreased SMN protein levels. To harness SMN2's ability to provide SMN function, two treatment strategies have been approved by the Food and Drug Administration (FDA), including an antisense oligonucleotide, nusinersen (Spinraza), and a small molecule, risdiplam (Evrysdi). Onasemnogene abeparvovec (Zolgensma) is an FDA-approved adeno-associated virus 9-mediated gene replacement therapy that creates a copy of the human SMN1 gene. In this review, we summarize the SMA etiology and FDA-approved therapies, and discuss the development of SMA therapeutic strategies and the challenges we faced.
脊髓性肌萎缩症（SMA）是一种隐性、神经退行性疾病。它是婴儿死亡的最常见遗传原因之一，其特征是肌肉无力、丧失行动能力和呼吸衰竭。SMA 主要由生存运动神经元 1（SMN1）基因的纯合缺失或突变引起。人类拥有第二个几乎相同的 SMN 拷贝，称为 SMN2 基因。尽管疾病严重程度与存在的 SMN2 拷贝数成反比，但它永远无法完全补偿 SMA 患者中 SMN1 的缺失；SMN2 仅表达功能性 SMN 转录本的一小部分。SMN 蛋白在人类细胞中无处不在，发挥着多种作用，从组装剪接体机制到自噬、RNA 代谢、信号转导、细胞内稳态、DNA 修复和重组。尽管潜在机制尚不清楚，但脊髓灰质前角细胞对 SMN 蛋白水平降低非常敏感。为了利用 SMN2 提供 SMN 功能的能力，两种治疗策略已被美国食品和药物管理局（FDA）批准，包括反义寡核苷酸 nusinersen（Spinraza）和小分子 risdiplam（Evrysdi）。onasemnogene abeparvovec（Zolgensma）是一种 FDA 批准的腺相关病毒 9 介导的基因替换疗法，可创建人类 SMN1 基因的副本。在这篇综述中，我们总结了 SMA 的病因和 FDA 批准的治疗方法，并讨论了 SMA 治疗策略的发展和我们面临的挑战。
