Base editing in humanized dystrophic mice.
Base editing in humanized dystrophic mice.
复制标题
人源化营养不良小鼠的碱基编辑。
DOI：
10.1016/j.omtn.2024.102185
复制
发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Han,Renzhi
中科院分区：
文献类型：
--
作者：
Zhang,Chen;Zhou,Yuan;Han,Renzhi
DMD的特征在于由肌营养不良蛋白基因突变引起的功能性肌营养不良蛋白的缺乏，导致进行性肌肉萎缩、心脏并发症和过早死亡。大的缺失突变占所有DMD病例的约70%。DMD的主要治疗努力集中在恢复功能性肌营养不良蛋白表达上。一种策略是通过腺相关病毒（AAV）递送被称为微肌营养不良蛋白的肌营养不良蛋白cDNA的小型化版本。2023年，美国食品药品监督管理局（FDA）对萨雷普塔的Elevidys（AAVrh. 74携带微小肌营养不良蛋白cDNA）。这是DMD基因治疗发展的一个重要里程碑。另一种策略利用反义寡核苷酸诱导靶向外显子跳跃并恢复肌营养不良蛋白基因的阅读框。外显子跳跃将DMD相关的框架破坏突变转化为贝克尔肌营养不良样缺失，这可以产生功能更强的截短型肌营养不良蛋白。第一个用于DMD外显子51跳跃的外显子跳跃药物eteplirsen于2016年获得FDA批准，随后是用于外显子53的VyonDys-53和viltolarsen以及用于外显子45跳跃的AmonDys-45。最近，CRISPR-Cas9基因编辑系统已经显示出永久恢复肌营养不良蛋白基因的阅读框架的巨大前景，正如许多临床前动物研究和细胞培养研究所证明的那样。3虽然大缺失是DMD最常见的原因，但据估计，无义突变约占10%-15%的病例。纠正这种无义突变可以采取不同的策略，有可能恢复全长肌营养不良蛋白的表达。一种策略涉及通过利用药理学试剂或工程化抑制性tRNA来调节翻译终止效率。4，5 Ataluren是一种促进核糖体提前终止密码子通读的恶二唑化合物，在欧洲和其他几个国家被批准用于治疗无义突变的DMD患者。
DMD is characterized by the absence of functional dystrophin protein resulting from mutations in the dystrophin gene, leading to progressive muscle wasting, cardiac complications, and premature mortality. Large deletion mutations account for approximately 70% of all DMD cases. The major therapeutic efforts for DMD are centered on restoring functional dystrophin expression. One strategy is to deliver a miniaturized version of dystrophin cDNA, known as micro-dystrophin, through adeno-associated virus (AAV). In 2023, the US Food and Drug Administration (FDA) granted accelerated approval for Sarepta’s Elevidys (AAVrh. 74 carrying micro-dystrophin cDNA) for patients with DMD who are 4–5 years of age. 2 This represents an important milestone in DMD gene therapy development. Another strategy utilizes antisense oligonucleotides to induce targeted exon skipping and restore the reading frame of the dystrophin gene. Exon skipping converts DMD-associated frame-disrupting mutations into Becker muscular dystrophy-like deletions, which can produce more functional, truncated dystrophin protein. The first exon-skipping drug for DMD exon 51 skipping, eteplirsen, received FDA approval in 2016, followed by VyonDys-53 and viltolarsen for exon 53 and AmonDys-45 for exon 45 skipping. More recently, the CRISPR-Cas9 gene editing system has shown great promise to permanently restore the reading frame of the dystrophin gene, as demonstrated by numerous preclinical animal studies and cell culture studies. 3While large deletions are the most common cause of DMD, nonsense mutations are estimated to account for approximately 10%–15% cases. Correcting such nonsense mutations could take different strategies, with the potential to restore full-length dystrophin expression. One strategy involves modulating translation termination efficiency through the utilization of pharmacological agents or engineered suppressor tRNAs. 4, 5 Ataluren, an oxadiazole compound facilitating ribosomal readthrough of premature stop codons, was approved to treat patients with DMD with nonsense mutations in European and several other countries.