Edinoff Amber N, Nguyen Long H, Odisho Amira S, Maxey Benjamin S, Pruitt John W, Girma Brook, Cornett Elyse M, Kaye Adam M, Kaye Alan D
Louisiana State University Health Science Center Shreveport.
Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific.
Orthop Rev (Pavia). 2021 Jun 19;13(2):24934. doi: 10.52965/001c.24934. eCollection 2021.
Spinal muscular atrophy (SMA) is a rare, autosomal recessive neuromuscular degenerative disease characterized by loss of spinal cord motor neurons leading to progressive muscle wasting. The most common pathology results from a homozygous disruption in the survival motor neuron 1 (SMN1) gene on chromosome 5q13 via deletion, conversion, or mutation. SMN2 is a near duplicate of SMN1 that can produce full-length SMN mRNA transcripts, but its overall production capability of these mRNA transcripts is lower than that seen in SMN1. This leads to lower levels of functional SMN protein within motor neurons. The FDA approved nusinersen in December 2016 to treat SMA associated with SMN1 gene mutation. It is administered directly to the central nervous system by intrathecal injection. An antisense oligonucleotide (ASO) drug, nusinersen, provides an upcoming and promising treatment option for SMA and represents a novel pharmacological approach with a mechanism of action relevant for other neurodegenerative disorders. Nusinersen begins with four initial loading doses that are followed by three maintenance doses per year. Three major studies (CHERISH, ENDEAR, and NURTURE) have shown to improve motor function in early and late-onset individuals and reduce the chances of ventilator requirements in pre-symptomatic infants. Studies investigating the timing of drug delivery in mouse models of SMA report the best outcomes when drugs are delivered early before any significant motor function is lost. Nusinersen is a novel therapeutic approach with consistent results in all three studies and is proof of the novel concept for treating SMA and other neurodegenerative disorders in the future.
脊髓性肌萎缩症（SMA）是一种罕见的常染色体隐性神经肌肉退行性疾病，其特征是脊髓运动神经元丧失，导致进行性肌肉萎缩。最常见的病理是5号染色体q13上的生存运动神经元1（SMN1）基因通过缺失、转换或突变发生纯合性破坏。SMN2是SMN1的近乎复制品，能够产生全长SMN mRNA转录本，但其这些mRNA转录本的总体产生能力低于SMN1。这导致运动神经元内功能性SMN蛋白水平降低。2016年12月，美国食品药品监督管理局（FDA）批准了诺西那生钠用于治疗与SMN1基因突变相关的SMA。它通过鞘内注射直接给药至中枢神经系统。诺西那生钠是一种反义寡核苷酸（ASO）药物，为SMA提供了一种即将出现且很有前景的治疗选择，代表了一种新的药理学方法，其作用机制与其他神经退行性疾病相关。诺西那生钠开始时给予四个初始负荷剂量，随后每年给予三个维持剂量。三项主要研究（CHERISH、ENDEAR和NURTURE）已表明可改善早发型和晚发型个体的运动功能，并降低症状前婴儿使用呼吸机的几率。在SMA小鼠模型中研究药物给药时间的研究报告称，在任何显著运动功能丧失之前尽早给药时效果最佳。诺西那生钠是一种新颖的治疗方法，在所有三项研究中均取得了一致的结果，是未来治疗SMA和其他神经退行性疾病这一新颖概念的证据。
