Talbot K, Tizzano E F
Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Department of Clinical and Molecular Genetics, Rare Diseases Unit, Hospital Valle Hebron, Barcelona, Spain.
Gene Ther. 2017 Sep;24(9):529-533. doi: 10.1038/gt.2017.52. Epub 2017 Jul 23.
Despite significant advances in basic research, the treatment of degenerative diseases of the nervous system remains one of the greatest challenges for translational medicine. The childhood onset motor neuron disorder spinal muscular atrophy (SMA) has been viewed as one of the more tractable targets for molecular therapy due to a detailed understanding of the molecular genetic basis of the disease. In SMA, inactivating mutations in the SMN1 gene can be partially compensated for by limited expression of SMN protein from a variable number of copies of the SMN2 gene, which provides both a molecular explanation for phenotypic severity and a target for therapy. The advent of the first tailored molecular therapy for SMA, based on modulating the splicing behaviour of the SMN2 gene provides, for the first time, a treatment which alters the natural history of motor neuron degeneration. Here we consider how this will change the landscape for diagnosis, clinical management and future therapeutic trials in SMA, as well as the implications for the molecular therapy of other neurological diseases.
尽管基础研究取得了重大进展，但神经系统退行性疾病的治疗仍然是转化医学面临的最大挑战之一。儿童期起病的运动神经元疾病脊髓性肌萎缩症（SMA），由于对该疾病分子遗传基础的详细了解，一直被视为分子治疗中较易处理的靶点之一。在SMA中，SMN1基因的失活突变可由SMN2基因多个拷贝的有限表达所产生的SMN蛋白部分补偿，这既为表型严重程度提供了分子解释，也为治疗提供了靶点。基于调节SMN2基因剪接行为的首个针对SMA的定制分子疗法的出现，首次提供了一种改变运动神经元变性自然病程的治疗方法。在此，我们探讨这将如何改变SMA的诊断、临床管理和未来治疗试验的格局，以及对其他神经疾病分子治疗的影响。
