Shababi Monir, Mattis Virginia B, Lorson Christian L
Department of Veterinary Pathobiology, University of Missouri, Columbia, MO, USA.
Drug News Perspect. 2010 Oct;23(8):475-82. doi: 10.1358/dnp.2010.23.8.1507295.
Spinal muscular atrophy (SMA) is the second most common autosomal recessive disease and is a leading cause of infantile death. This disease has a carrier frequency of 1:35, affecting 1/6,000 live births and is the result of a homozygous loss of the survival of motor neuron 1 gene (SMN1). Humans carry a nearly identical copy gene, SMN2, that codes for very low levels of the full-length protein, ∼10% when compared to SMN1. This is due to one silent nucleotide transition at the 5' end of exon 7 that disrupts a critical splicing regulatory domain. The underlying protein coding region, however, is unaffected by this and other nucleotide differences between SMN1 and SMN2. SMN2 has, therefore, been envisioned as an outstanding target for therapeutic strategies that 1) increases SMN2 expression, 2) alters the pre-messenger RNA splicing of exon 7 or 3) stabilizes the SMN2-derived protein products. In this review, we summarize numerous therapeutic approaches including nucleic acid-based and drug-oriented therapies that have progressed toward treating SMA.
脊髓性肌萎缩症（SMA）是第二常见的常染色体隐性疾病，也是婴儿死亡的主要原因。这种疾病的携带者频率为1:35，每6000例活产婴儿中就有1例受影响，它是运动神经元存活1基因（SMN1）纯合缺失的结果。人类携带一个几乎相同的拷贝基因SMN2，该基因编码的全长蛋白水平极低，与SMN1相比约为10%。这是由于外显子7 5'端的一个沉默核苷酸转换破坏了一个关键的剪接调节域。然而，潜在的蛋白质编码区域不受此影响，也不受SMN1和SMN2之间其他核苷酸差异的影响。因此，SMN2被视为治疗策略的一个理想靶点，这些策略包括：1）增加SMN2的表达；2）改变外显子7的信使前体RNA剪接；或3）稳定SMN2衍生的蛋白质产物。在这篇综述中，我们总结了多种治疗方法，包括已在治疗SMA方面取得进展的基于核酸的疗法和药物疗法。
