Department of Veterinary Pathobiology, Bond Life Sciences Center, College of Veterinary Medicine, University of Missouri, Columbia, MO, 65201, USA.
Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
Sci Rep. 2019 Feb 7;9(1):1633. doi: 10.1038/s41598-018-38208-9.
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder that causes progressive muscle weakness and is the leading genetic cause of infant mortality worldwide. SMA is caused by the loss of survival motor neuron 1 (SMN1). In humans, a nearly identical copy gene is present, called SMN2. Although SMN2 maintains the same coding sequence, this gene cannot compensate for the loss of SMN1 because of a single silent nucleotide difference in SMN2 exon 7. SMN2 primarily produces an alternatively spliced isoform lacking exon 7, which is critical for protein function. SMN2 is an important disease modifier that makes for an excellent target for therapeutic intervention because all SMA patients retain SMN2. Therefore, compounds and small molecules that can increase SMN2 exon 7 inclusion, transcription and SMN protein stability have great potential for SMA therapeutics. Previously, we performed a high throughput screen and established a class of compounds that increase SMN protein in various cellular contexts. In this study, a novel compound was identified that increased SMN protein levels in vivo and ameliorated the disease phenotype in severe and intermediate mouse models of SMA.
脊髓性肌萎缩症（SMA）是一种常染色体隐性神经退行性疾病，可导致进行性肌肉无力，是全球婴儿死亡的主要遗传原因。SMA 是由运动神经元存活 1 号（SMN1）缺失引起的。在人类中，存在一个几乎相同的拷贝基因，称为 SMN2。尽管 SMN2 保持相同的编码序列，但由于 SMN2 外显子 7 中的一个单一沉默核苷酸差异，该基因无法弥补 SMN1 的缺失。SMN2 主要产生一种缺乏外显子 7 的剪接异构体，这对于蛋白质功能至关重要。SMN2 是一种重要的疾病修饰因子，是治疗干预的理想靶点，因为所有 SMA 患者都保留了 SMN2。因此，能够增加 SMN2 外显子 7 包含、转录和 SMN 蛋白稳定性的化合物和小分子在 SMA 治疗中有很大的潜力。此前，我们进行了高通量筛选，并在各种细胞环境中建立了一类可增加 SMN 蛋白的化合物。在这项研究中，鉴定出一种新的化合物，可在体内增加 SMN 蛋白水平，并改善严重和中度 SMA 小鼠模型的疾病表型。
