Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, 1060 Carmack Road, Columbus, OH 43210, USA.
Department of Neurology, Neuromuscular Division, The Ohio State University Wexner Medical Center, 395 W. 12(th) Ave, Columbus, OH 43210, USA.
Neurobiol Dis. 2021 Nov;159:105488. doi: 10.1016/j.nbd.2021.105488. Epub 2021 Aug 20.
Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by survival motor neuron (SMN) protein deficiency which results in motor neuron loss and muscle atrophy. SMA is caused by a mutation or deletion of the survival motor neuron 1 (SMN1) gene and retention of the nearly identical SMN2 gene. SMN2 contains a C to T change in exon 7 that results in exon 7 exclusion from 90% of transcripts. SMN protein lacking exon 7 is unstable and rapidly degraded. The remaining full-length transcripts from SMN2 are insufficient for normal motor neuron function leading to the development of SMA. Three different therapeutic approaches that increase full-length SMN (FL-SMN) protein production are approved for treatment of SMA patients. Studies in both animal models and humans have demonstrated increasing SMN levels prior to onset of symptoms provides the greatest therapeutic benefit. Treatment of SMA, after some motor neuron loss has occurred, is also effective but to a lesser degree. The SMN∆7 mouse model is a well characterized model of severe or type 1 SMA, dying at 14 days of age. Here we treated three groups of ∆7SMA mice starting before, roughly during, and after symptom onset to determine if combining two mechanistically distinct SMN inducing therapies could improve the therapeutic outcome both before and after motor neuron loss. We found, compared with individual therapies, that morpholino antisense oligonucleotide (ASO) directed against ISS-N1 combined with the small molecule compound RG7800 significantly increased FL-SMN transcript and protein production resulting in improved survival and weight of ∆7SMA mice. Moreover, when give late symptomatically, motor unit function was completely rescued with no loss in function at 100 days of age in the dual treatment group. We have therefore shown that this dual therapeutic approach successfully increases SMN protein and rescues motor function in symptomatic ∆7SMA mice.
脊髓性肌萎缩症（SMA）是一种常染色体隐性疾病，其特征是生存运动神经元（SMN）蛋白缺乏，导致运动神经元丢失和肌肉萎缩。SMA 是由生存运动神经元 1（SMN1）基因的突变或缺失以及几乎相同的 SMN2 基因的保留引起的。SMN2 在外显子 7 中含有 C 到 T 的变化，导致 90%的转录物中外显子 7 的缺失。缺乏外显子 7 的 SMN 蛋白不稳定且迅速降解。SMN2 中剩余的全长转录本不足以维持正常运动神经元功能，从而导致 SMA 的发生。三种不同的增加全长 SMN（FL-SMN）蛋白产生的治疗方法已被批准用于治疗 SMA 患者。在动物模型和人类中的研究表明，在症状出现之前增加 SMN 水平可提供最大的治疗益处。在一些运动神经元丢失发生后，治疗 SMA 也是有效的，但效果较小。SMN∆7 小鼠模型是一种经过充分表征的严重或 1 型 SMA 模型，在 14 天大时死亡。在这里，我们在症状出现之前、期间和之后开始治疗三组 ∆7SMA 小鼠，以确定两种机制上不同的 SMN 诱导疗法是否可以在运动神经元丢失之前和之后改善治疗效果。我们发现，与单独治疗相比，针对 ISS-N1 的反义寡核苷酸（ASO）与小分子化合物 RG7800 联合使用可显著增加 FL-SMN 转录物和蛋白质的产生，从而提高 ∆7SMA 小鼠的存活率和体重。此外，当在症状后期给予时，双重治疗组在 100 天大时运动单位功能完全恢复，没有功能丧失。因此，我们已经表明，这种双重治疗方法可成功增加 SMN 蛋白并挽救有症状的 ∆7SMA 小鼠的运动功能。
