Motohashi Norio, Tsukahara Toshifumi, Aoki Yoshitsugu
Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan.
Area of Bioscience and Biotechnology, School of Materials Science, Japan Advanced Institute of Science and Technology (JAIST), Ishikawa, Japan.
Front Genome Ed. 2022 May 10;4:863651. doi: 10.3389/fgeed.2022.863651. eCollection 2022.
Approval of therapeutic RNA molecules, including RNA vaccines, has paved the way for next-generation treatment strategies for various diseases. Oligonucleotide-based therapeutics hold particular promise for treating incurable muscular dystrophies, including Duchenne muscular dystrophy (DMD). DMD is a severe monogenic disease triggered by deletions, duplications, or point mutations in the gene, which encodes a membrane-linked cytoskeletal protein to protect muscle fibers from contraction-induced injury. Patients with DMD inevitably succumb to muscle degeneration and atrophy early in life, leading to premature death from cardiac and respiratory failure. Thus far, the disease has thwarted all curative strategies. Transcriptomic manipulation, employing exon skipping using antisense oligonucleotides (ASO), has made significant progress in the search for DMD therapeutics. Several exon-skipping drugs employing RNA manipulation technology have been approved by regulatory agencies and have shown promise in clinical trials. This review summarizes recent scientific and clinical progress of ASO and other novel RNA manipulations, including RNA-based editing using MS2 coat protein-conjugated adenosine deaminase acting on the RNA (MCP-ADAR) system illustrating the efficacy and limitations of therapies to restore dystrophin. Perhaps lessons from this review will encourage the application of RNA-editing therapy to other neuromuscular disorders.
包括RNA疫苗在内的治疗性RNA分子的获批，为各种疾病的下一代治疗策略铺平了道路。基于寡核苷酸的疗法在治疗包括杜氏肌营养不良症（DMD）在内的无法治愈的肌肉营养不良症方面具有特别的前景。DMD是一种严重的单基因疾病，由编码一种与膜相连的细胞骨架蛋白以保护肌纤维免受收缩诱导损伤的基因中的缺失、重复或点突变引发。DMD患者不可避免地在生命早期就会出现肌肉退化和萎缩，导致因心脏和呼吸衰竭而过早死亡。到目前为止，这种疾病挫败了所有的治疗策略。采用反义寡核苷酸（ASO）进行外显子跳跃的转录组操作，在寻找DMD治疗方法方面取得了重大进展。几种采用RNA操作技术的外显子跳跃药物已获得监管机构的批准，并在临床试验中显示出前景。本综述总结了ASO和其他新型RNA操作的最新科学和临床进展，包括使用与MS2外壳蛋白偶联的作用于RNA的腺苷脱氨酶（MCP-ADAR）系统进行基于RNA的编辑，阐述了恢复抗肌萎缩蛋白疗法的疗效和局限性。也许本综述中的经验教训将鼓励RNA编辑疗法应用于其他神经肌肉疾病。
