Shiryaeva Olga, Tolochko Christina, Alekseeva Tatiana, Dyachuk Vyacheslav
Almazov Federal Medical Research Centre, 197341 Saint Petersburg, Russia.
Int J Mol Sci. 2025 Apr 25;26(9):4063. doi: 10.3390/ijms26094063.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons, which causes muscle atrophy. Genetic forms of ALS are recorded only in 10% of cases. However, over the past decade, studies in genetics have substantially contributed to our understanding of the molecular mechanisms underlying ALS. The identification of key mutations such as , , , and has led to the development of targeted therapy that is gradually being introduced into clinical trials, opening up a broad range of opportunities for correcting these mutations. In this review, we aimed to present an extensive overview of the currently known mechanisms of motor neuron degeneration associated with mutations in these genes and also the gene therapy methods for inhibiting the expression of their mutant proteins. Among these, antisense oligonucleotides, RNA interference (siRNA and miRNA), and gene-editing (CRISPR/Cas9) methods are of particular interest. Each has shown its efficacy in animal models when targeting mutant genes, whereas some of them have proven to be efficient in human clinical trials.
肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，其特征是运动神经元选择性死亡，导致肌肉萎缩。仅10%的病例记录为遗传性ALS。然而，在过去十年中，遗传学研究极大地促进了我们对ALS潜在分子机制的理解。诸如 、 、 和 等关键突变的鉴定导致了靶向治疗的发展，这种治疗正逐渐引入临床试验，为纠正这些突变开辟了广泛的机会。在这篇综述中，我们旨在全面概述目前已知的与这些基因突变相关的运动神经元变性机制，以及抑制其突变蛋白表达的基因治疗方法。其中，反义寡核苷酸、RNA干扰（siRNA和miRNA）以及基因编辑（CRISPR/Cas9）方法尤其令人关注。在针对突变基因时，每种方法在动物模型中都显示出了疗效，而其中一些方法已在人类临床试验中被证明是有效的。
