Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, A.C. Meyers Vænge 15, 2450 Copenhagen, Denmark.
Neumirna Therapeutics, A.C. Meyers Vænge 15, 2450 Copenhagen, Denmark.
RNA Biol. 2022;19(1):594-608. doi: 10.1080/15476286.2022.2066334. Epub 2021 Dec 31.
RNA therapeutics comprise a diverse group of oligonucleotide-based drugs such as antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and short hairpin RNAs (shRNAs) that can be designed to selectively interact with drug targets currently undruggable with small molecule-based drugs or monoclonal antibodies. Furthermore, RNA-based therapeutics have the potential to modulate entire disease pathways, and thereby represent a new modality with unprecedented potential for generating disease-modifying drugs for a wide variety of human diseases, including central nervous system (CNS) disorders. Here, we describe different strategies for delivering RNA drugs to the CNS and review recent advances in clinical development of ASO drugs and siRNA-based therapeutics for the treatment of neurological diseases and neuromuscular disorders. 2'-MOE: 2'--(2-methoxyethyl); 2'--Me: 2'--methyl; 2'-F: 2'-fluoro; AD: Alzheimer's disease; ALS: Amyotrophic lateral sclerosis; ALSFRS-R: Revised Amyotrophic Lateral Sclerosis Functional Rating Scale; ARC: Antibody siRNA Conjugate; AS: Angelman Syndrome; ASGRP: Asialoglycoprotein receptor; ASO: Antisense oligonucleotide; AxD: Alexander Disease; BBB: Blood brain barrier; Bp: Basepair; CNM: Centronuclear myopathies; CNS: Central Nervous System; CPP: Cell-penetrating Peptide; CSF: Cerebrospinal fluid; DMD: Duchenne muscular dystrophy; DNA: Deoxyribonucleic acid; FAP: Familial amyloid polyneuropathy; FALS: Familial amyotrophic lateral sclerosis; FDA: The United States Food and Drug Administration; GalNAc: N-acetylgalactosamine; GoF: Gain of function; hATTR: Hereditary transthyretin amyloidosis; HD: Huntington's disease; HRQOL: health-related quality of life; ICV: Intracerebroventricular; IT: Intrathecal; LNA: Locked nucleic acid; LoF: Loss of function; mRNA: Messenger RNA; MS: Multiple Sclerosis; MSA: Multiple System Atrophy; NBE: New Biological Entity; NCE: New Chemical Entity; NHP: Nonhuman primate; nt: Nucleotide; PD: Parkinson's disease; PNP: Polyneuropathy; PNS: Peripheral nervous system; PS: Phosphorothioate; RISC: RNA-Induced Silencing Complex; RNA: Ribonucleic acid; RNAi: RNA interference; s.c.: Subcutaneous; siRNA: Small interfering RNA; SMA: Spinal muscular atrophy; SMN: Survival motor neuron; TTR: Transthyretin.
RNA 疗法包括一大类基于寡核苷酸的药物，如反义寡核苷酸 (ASO)、小干扰 RNA (siRNA) 和短发夹 RNA (shRNA)，它们可以被设计为选择性地与目前用小分子药物或单克隆抗体无法治疗的药物靶点相互作用。此外，基于 RNA 的疗法有可能调节整个疾病途径，从而代表一种新的模式，具有前所未有的潜力为包括中枢神经系统 (CNS) 疾病在内的各种人类疾病产生可改变疾病的药物。在这里，我们描述了将 RNA 药物递送到 CNS 的不同策略，并回顾了 ASO 药物和基于 siRNA 的疗法在治疗神经疾病和神经肌肉疾病的临床开发中的最新进展。2'-MOE：2'--(2-甲氧基乙基)；2'-Me：2'-甲基；2'-F：2'-氟；AD：阿尔茨海默病；ALS：肌萎缩侧索硬化症；ALSFRS-R：修订肌萎缩侧索硬化症功能评定量表；ARC：抗体 siRNA 缀合物；AS：安格曼综合征；ASGRP：去唾液酸糖蛋白受体；ASO：反义寡核苷酸；AxD：亚历山大病；BBB：血脑屏障；Bp：碱基对；CNM：中核肌病；CNS：中枢神经系统；CPP：细胞穿透肽；CSF：脑脊液；DMD：杜氏肌营养不良症；DNA：脱氧核糖核酸；FAP：家族性淀粉样多神经病；FALS：家族性肌萎缩侧索硬化症；FDA：美国食品和药物管理局；GalNAc：N-乙酰半乳糖胺；GoF：功能获得；hATTR：遗传性转甲状腺素淀粉样变性；HD：亨廷顿病；HRQOL：健康相关生活质量；ICV：脑室内；IT：鞘内；LNA：锁核酸；LoF：功能丧失；mRNA：信使 RNA；MS：多发性硬化症；MSA：多系统萎缩症；NBE：新型生物实体；NCE：新型化学实体；NHP：非人灵长类动物；nt：核苷酸；PD：帕金森病；PNP：多发性神经病；PNS：周围神经系统；PS：硫代磷酸酯；RISC：RNA 诱导沉默复合物；RNA：核糖核酸；RNAi：RNA 干扰；s.c.：皮下；siRNA：小干扰 RNA；SMA：脊髓性肌萎缩症；SMN：生存运动神经元；TTR：转甲状腺素。
