Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, via Francesco Sforza 35, 20122 Milan, Italy.
Int J Mol Sci. 2018 Jan 6;19(1):167. doi: 10.3390/ijms19010167.
Spinal muscular atrophy (SMA) is an autosomal-recessive childhood motor neuron disease and the main genetic cause of infant mortality. SMA is caused by deletions or mutations in the survival motor neuron 1 () gene, which results in SMN protein deficiency. Only one approved drug has recently become available and allows for the correction of aberrant splicing of the paralogous gene by antisense oligonucleotides (ASOs), leading to production of full-length SMN protein. We have already demonstrated that a sequence of an ASO variant, Morpholino (MO), is particularly suitable because of its safety and efficacy profile and is both able to increase SMN levels and rescue the murine SMA phenotype. Here, we optimized this strategy by testing the efficacy of four new MO sequences targeting . Two out of the four new MO sequences showed better efficacy in terms of SMN protein production both in SMA induced pluripotent stem cells (iPSCs) and SMAΔ7 mice. Further, the effect was enhanced when different MO sequences were administered in combination. Our data provide an important insight for MO-based treatment for SMA. Optimization of the target sequence and validation of a treatment based on a combination of different MO sequences could support further pre-clinical studies and the progression toward future clinical trials.
脊髓性肌萎缩症（SMA）是一种常染色体隐性儿童运动神经元疾病，也是婴儿死亡的主要遗传原因。SMA 是由生存运动神经元 1 （SMN1）基因缺失或突变引起的，导致 SMN 蛋白缺乏。最近只有一种批准的药物可用，该药物通过反义寡核苷酸（ASO）允许纠正同源基因的异常剪接，从而产生全长 SMN 蛋白。我们已经证明，一种 ASO 变体（Morpholino，MO）的序列特别适合，因为它具有安全性和疗效特征，既能提高 SMN 水平，又能挽救 SMA 表型。在这里，我们通过测试针对 的四种新 MO 序列的疗效来优化该策略。在 SMA 诱导多能干细胞（iPSC）和 SMAΔ7 小鼠中，四种新 MO 序列中的两种在 SMN 蛋白产生方面显示出更好的疗效。此外，当不同的 MO 序列联合给药时，效果会增强。我们的数据为基于 MO 的 SMA 治疗提供了重要的见解。优化靶序列并验证基于不同 MO 序列组合的治疗方法可以支持进一步的临床前研究和未来临床试验的进展。
