Brunet de Courssou Jean-Baptiste, Durr Alexandra, Adams David, Corvol Jean-Christophe, Mariani Louise-Laure
Assistance Publique Hôpitaux de Paris, Department of Neurology, CIC Neurosciences, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
Sorbonne University, Paris Brain Institute - ICM, Inserm, CNRS, Paris, France.
Brain. 2022 Apr 29;145(3):816-831. doi: 10.1093/brain/awab423.
Advances in targeted regulation of gene expression allowed new therapeutic approaches for monogenic neurological diseases. Molecular diagnosis has paved the way to personalized medicine targeting the pathogenic roots: DNA or its RNA transcript. These antisense therapies rely on modified nucleotides sequences (single-strand DNA or RNA, both belonging to the antisense oligonucleotides family, or double-strand interfering RNA) to act specifically on pathogenic target nucleic acids, thanks to complementary base pairing. Depending on the type of molecule, chemical modifications and target, base pairing will lead alternatively to splicing modifications of primary transcript RNA or transient messenger RNA degradation or non-translation. The key to success for neurodegenerative diseases also depends on the ability to reach target cells. The most advanced antisense therapies under development in neurological disorders are presented here, at the clinical stage of development, either at phase 3 or market authorization stage, such as in spinal amyotrophy, Duchenne muscular dystrophy, transthyretin-related hereditary amyloidosis, porphyria and amyotrophic lateral sclerosis; or in earlier clinical phase 1 B, for Huntington's disease, synucleinopathies and tauopathies. We also discuss antisense therapies at the preclinical stage, such as in some tauopathies, spinocerebellar ataxias or other rare neurological disorders. Each subtype of antisense therapy, antisense oligonucleotides or interfering RNA, has proved target engagement or even clinical efficacy in patients; undisputable recent advances for severe and previously untreatable neurological disorders. Antisense therapies show great promise, but many unknowns remain. Expanding the initial successes achieved in orphan or rare diseases to other disorders will be the next challenge, as shown by the recent failure in Huntington disease or due to long-term preclinical toxicity in multiple system atrophy and cystic fibrosis. This will be critical in the perspective of new planned applications to premanifest mutation carriers, or other non-genetic degenerative disorders such as multiple system atrophy or Parkinson disease.
基因表达靶向调控技术的进展为单基因神经疾病带来了新的治疗方法。分子诊断为针对致病根源（DNA或其RNA转录本）的个性化医疗铺平了道路。这些反义疗法依靠修饰的核苷酸序列（单链DNA或RNA，均属于反义寡核苷酸家族，或双链干扰RNA），通过互补碱基配对特异性作用于致病靶核酸。根据分子类型、化学修饰和靶标的不同，碱基配对可导致初级转录RNA的剪接修饰、信使RNA的瞬时降解或翻译抑制。神经退行性疾病治疗成功的关键还取决于能否到达靶细胞。本文介绍了正在研发的、处于临床开发阶段（3期或上市许可阶段）的最先进的反义疗法，如脊髓性肌萎缩症、杜氏肌营养不良症、转甲状腺素蛋白相关遗传性淀粉样变性、卟啉病和肌萎缩侧索硬化症；以及处于更早临床1B期的亨廷顿舞蹈病、突触核蛋白病和tau蛋白病。我们还讨论了临床前阶段的反义疗法，如某些tau蛋白病、脊髓小脑共济失调或其他罕见神经疾病。反义疗法的每种亚型，即反义寡核苷酸或干扰RNA，都已在患者中证明了靶点结合甚至临床疗效；这是严重且以前无法治疗的神经疾病取得的无可争议的最新进展。反义疗法前景广阔，但仍有许多未知之处。将在孤儿病或罕见病中取得的初步成功扩展到其他疾病将是下一个挑战，最近亨廷顿舞蹈病治疗失败或多系统萎缩症和囊性纤维化长期临床前毒性问题就说明了这一点。这对于新计划应用于症状前突变携带者或其他非遗传性退行性疾病（如多系统萎缩症或帕金森病）至关重要。
