Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA; email:
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21202, USA.
Annu Rev Med. 2021 Jan 27;72:1-14. doi: 10.1146/annurev-med-070119-115459.
The last few decades have seen an explosion in identification of genes that cause monogenetic neurological diseases, as well as advances in gene-targeting therapeutics. Neurological conditions that were once considered incurable are now increasingly tractable. At the forefront is the motor neuron disease spinal muscular atrophy (SMA), historically the leading inherited cause of infant mortality. In the last 5 years, three SMA treatments have been approved by the US Food and Drug Administration (FDA): intrathecally delivered splice-switching antisense oligonucleotide (nusinersen), systemically delivered AAV9-based gene replacement therapy (onasemnogene abeparvovec), and an orally bioavailable, small-molecule, splice-switching drug (risdiplam). Despite this remarkable progress, clinical outcomes in patients are variable. Therapeutic optimization will require improved understanding of drug pharmacokinetics and target engagement in neurons, potential toxicities, and long-term effects. We review current progress in SMA therapeutics, clinical trials, shortcomings of current treatments, and implications for the treatment of other neurogenetic diseases.
过去几十年见证了大量单基因神经疾病相关基因的鉴定，以及基因靶向治疗的进步。曾经被认为无法治愈的神经疾病现在越来越容易治疗。处于最前沿的是运动神经元疾病脊髓性肌萎缩症（SMA），它曾是导致婴儿死亡的主要遗传性病因。在过去 5 年中，三种 SMA 治疗方法已获得美国食品和药物管理局（FDA）批准：鞘内注射剪接转换反义寡核苷酸（nusinersen）、全身递送基于 AAV9 的基因替代疗法（onasemnogene abeparvovec），以及一种口服生物利用度的小分子剪接转换药物（risdiplam）。尽管取得了这一显著进展，但患者的临床结局仍存在差异。治疗优化需要深入了解药物在神经元中的药代动力学和靶标结合情况、潜在毒性和长期影响。我们综述 SMA 治疗学的当前进展、临床试验、现有治疗方法的局限性，以及对其他神经遗传疾病治疗的启示。
