Institute for Clinical Neurobiology, University of Wuerzburg, Wuerzburg, Germany.
Nat Neurosci. 2010 Jul;13(7):795-9. doi: 10.1038/nn.2565.
Proximal spinal muscular atrophy (SMA) is the predominant form of motor neuron disease in children and young adults. In contrast to other neurodegenerative disorders, SMA is a genetically homozygous autosomal recessive disease that is caused by deficiency of the survival motor neuron (SMN) protein. This homogeneity should in principle facilitate therapy development. Previous therapy approaches have focused on upregulation of SMN expression from a second SMN (SMN2) gene that gives rise to low amounts of functional SMN protein. Drug development to target disease-specific mechanisms at cellular and physiological levels is in its early stages, as the pathophysiological processes that underlie the main disease symptoms are still not fully understood. Mouse models have helped to make conceptual progress in the disease mechanism, but their suitability in the search for therapeutic agents remains to be validated--an issue that is ubiquitous to the translational therapeutic research of other neurodegenerative diseases. Human induced pluripotent stem cell technology for generation of large numbers of human motor neurons could help to fill this gap and advance the power of drug screening. In parallel, advances in oligonucleotide technologies for engineering SMN2 pre-mRNA splicing are approaching their first clinical trials, whose success depends on improved technologies for drug delivery to motor neurons. If this obstacle can be overcome, this could boost therapy development, not only for SMA but also for other neurodegenerative disorders.
脊髓性肌萎缩症（SMA）是儿童和青年期运动神经元病的主要形式。与其他神经退行性疾病不同，SMA 是一种由生存运动神经元（SMN）蛋白缺乏引起的纯合子常染色体隐性遗传疾病。这种同质性原则上应该有助于治疗的发展。以前的治疗方法主要集中在从第二个 SMN（SMN2）基因上调 SMN 表达，该基因产生低量的功能性 SMN 蛋白。针对细胞和生理水平上特定疾病机制的药物开发仍处于早期阶段，因为导致主要疾病症状的病理生理过程仍不完全清楚。小鼠模型在疾病机制方面取得了概念上的进展，但它们在寻找治疗剂方面的适用性仍有待验证——这是其他神经退行性疾病转化治疗研究中普遍存在的问题。用于生成大量人类运动神经元的人类诱导多能干细胞技术可以帮助填补这一空白，并提高药物筛选的能力。与此同时，用于工程 SMN2 前体 mRNA 剪接的寡核苷酸技术的进步正在接近他们的首次临床试验，其成功取决于向运动神经元输送药物的技术的改进。如果这一障碍能够克服，这不仅将促进 SMA 的治疗发展，也将促进其他神经退行性疾病的治疗发展。
