Wood Matthew J A, Talbot Kevin, Bowerman Melissa
Department of Physiology, Anatomy and Genetics, University of Oxford OX1 3QX, Oxford, UK.
Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
Hum Mol Genet. 2017 Oct 1;26(R2):R151-R159. doi: 10.1093/hmg/ddx215.
Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by loss of spinal cord motor neurons, muscle atrophy and infantile death or severe disability. It is caused by severe reduction of the ubiquitously expressed survival motor neuron (SMN) protein, owing to loss of the SMN1 gene. This would be completely incompatible with survival without the presence of a quasi-identical duplicated gene, SMN2, specific to humans. SMN2 harbours a silent point mutation that favours the production of transcripts lacking exon 7 and a rapidly degraded non-functional SMNΔ7 protein, but from which functional full length SMN protein is produced at very low levels (∼10%). Since the seminal discovery of the SMA-causing gene in 1995, research has focused on the development of various SMN replacement strategies culminating, in December 2016, in the approval of the first precise molecularly targeted therapy for SMA (nusinersen), and a pivotal proof of principle that therapeutic antisense oligonucleotide (ASO) treatment can effectively target the central nervous system (CNS) to treat neurological and neuromuscular disease. Nusinersen is a steric block ASO that binds the SMN2 messenger RNA and promotes exon 7 inclusion and thus increases full length SMN expression. Here, we consider the implications of this therapeutic landmark for SMA therapeutics and discuss how future developments will need to address the challenges of delivering ASO therapies to the CNS, with appropriate efficiency and activity, and how SMN-based therapy should be used in combination with complementary strategies to provide an integrated approach to treat CNS and peripheral pathologies in SMA.
脊髓性肌萎缩症（SMA）是一种毁灭性的神经肌肉疾病，其特征为脊髓运动神经元丧失、肌肉萎缩以及婴儿死亡或严重残疾。它是由普遍表达的生存运动神经元（SMN）蛋白严重减少所致，原因是SMN1基因缺失。若没有人类特有的几乎相同的重复基因SMN2，这种情况将完全无法存活。SMN2存在一个沉默点突变，该突变有利于产生缺乏外显子7的转录本以及一种迅速降解的无功能SMNΔ7蛋白，但也能以非常低的水平（约10%）产生功能性全长SMN蛋白。自1995年发现导致SMA的基因以来，研究一直聚焦于各种SMN替代策略的开发，最终在2016年12月，首个针对SMA的精确分子靶向疗法（诺西那生钠）获批，这是一个关键的原理验证，即治疗性反义寡核苷酸（ASO）治疗可有效靶向中枢神经系统（CNS）以治疗神经和神经肌肉疾病。诺西那生钠是一种空间位阻ASO，它与SMN2信使核糖核酸结合并促进外显子7的包含，从而增加全长SMN的表达。在此，我们考虑这一治疗里程碑对SMA治疗的影响，并讨论未来的发展将如何应对以适当的效率和活性将ASO疗法递送至CNS的挑战，以及基于SMN的疗法应如何与互补策略联合使用，以提供一种综合方法来治疗SMA中的中枢神经系统和周围病变。
