Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
The Friends of Garrett Cumming Research & Muscular Dystrophy Canada HM Toupin Neurological Sciences Research, Edmonton, AB T6G 2H7, Canada.
Molecules. 2024 Jun 4;29(11):2658. doi: 10.3390/molecules29112658.
Spinal muscular atrophy (SMA) is a severe neuromuscular disorder that is caused by mutations in the survival motor neuron 1 () gene, hindering the production of functional survival motor neuron (SMN) proteins. Antisense oligonucleotides (ASOs), a versatile DNA-like drug, are adept at binding to target RNA to prevent translation or promote alternative splicing. Nusinersen is an FDA-approved ASO for the treatment of SMA. It effectively promotes alternative splicing in pre-mRNA transcribed from the gene, an analog of the gene, to produce a greater amount of full-length SMN protein, to compensate for the loss of functional protein translated from . Despite its efficacy in ameliorating SMA symptoms, the cellular uptake of these ASOs is suboptimal, and their inability to penetrate the CNS necessitates invasive lumbar punctures. Cell-penetrating peptides (CPPs), which can be conjugated to ASOs, represent a promising approach to improve the efficiency of these treatments for SMA and have the potential to transverse the blood-brain barrier to circumvent the need for intrusive intrathecal injections and their associated adverse effects. This review provides a comprehensive analysis of ASO therapies, their application for the treatment of SMA, and the encouraging potential of CPPs as delivery systems to improve ASO uptake and overall efficiency.
脊髓性肌萎缩症（SMA）是一种严重的神经肌肉疾病，由生存运动神经元 1 （SMN1）基因的突变引起，阻碍了功能性生存运动神经元（SMN）蛋白的产生。反义寡核苷酸（ASO）是一种多功能的类似 DNA 的药物，擅长与靶 RNA 结合，以防止翻译或促进选择性剪接。nusinersen 是一种经美国食品和药物管理局（FDA）批准用于治疗 SMA 的 ASO。它能有效地促进由 基因转录的前体 mRNA 的选择性剪接，产生更多全长 SMN 蛋白，以补偿从 基因翻译的功能性蛋白的丧失。尽管它能有效改善 SMA 症状，但这些 ASO 的细胞摄取效果不佳，而且它们无法穿透中枢神经系统，需要进行侵入性腰椎穿刺。细胞穿透肽（CPP）可以与 ASO 结合，是提高这些 SMA 治疗方法效率的一种很有前途的方法，并且有可能穿过血脑屏障，避免需要侵入性的鞘内注射及其相关的不良反应。这篇综述全面分析了 ASO 疗法、它们在 SMA 治疗中的应用，以及 CPP 作为递送系统提高 ASO 摄取和整体效率的令人鼓舞的潜力。
