Duchenne肌营养不良是一种破坏性疾病,可导致进行性肌肉损失和过早死亡。虽然医疗管理主要侧重于对症治疗,几十年的研究已经产生了第一种疗法,能够恢复受影响的肌营养不良蛋白转录本的阅读框或从载体诱导截短的肌营养不良蛋白的合成,在临床前或临床开发中使用基于基因治疗和细胞信号传导的其他策略。然而,最近的报道显示,潜在的治疗性肌营养不良蛋白在患者体内可能具有免疫原性.这就提出了一个问题,即肌萎缩蛋白是否类似,utrophin,可能是更合适的治疗蛋白.这里,我们比较了肌养蛋白和肌养蛋白的氨基酸序列和结构,将公布的数据与我们扩展的计算机模拟分析相结合。然后,我们在Duchenne肌营养不良的治疗方法的背景下讨论这些结果。具体来说,我们专注于基于微肌营养不良蛋白和微素基因与重组腺相关病毒载体的传递策略,突变的肌营养不良蛋白前mRNA的外显子跳跃,用掩盖过早终止密码子的小分子阅读终止密码子,通过成簇的规则间隔短回文重复序列(CRISPR)/CRISPR相关蛋白9(CRISPR/Cas9)介导的基因工程修复肌营养不良蛋白基因,和增加的乌罗素水平。我们的分析强调了Duchenne肌营养不良治疗中各种肌营养不良蛋白和营养蛋白结构域的重要性,提供对设计具有改善的功效和降低的免疫反应性的新型治疗化合物的见解。虽然必需的肌动蛋白和β-营养不良聚糖结合位点存在于两种蛋白质中,在这些结构域中可以识别出重要的功能差异,截短的肌营养不良蛋白的一些其他部分可能由于其潜在的免疫原性而需要重新设计。或者,基于营养素的疗法可能提供一种更安全、更有效的方法.
Duchenne muscular dystrophy is a devastating disease that leads to progressive muscle loss and premature death. While medical management focuses mostly on symptomatic treatment, decades of research have resulted in first therapeutics able to restore the affected reading frame of dystrophin transcripts or induce synthesis of a truncated dystrophin protein from a vector, with other strategies based on gene therapy and cell signaling in preclinical or clinical development. Nevertheless, recent reports show that potentially therapeutic dystrophins can be immunogenic in patients. This raises the question of whether a dystrophin paralog,
utrophin, could be a more suitable therapeutic protein. Here, we compare dystrophin and
utrophin amino acid sequences and structures, combining published data with our extended in silico analyses. We then discuss these results in the context of therapeutic approaches for Duchenne muscular dystrophy. Specifically, we focus on strategies based on delivery of micro-dystrophin and micro-
utrophin genes with recombinant adeno-associated viral vectors, exon skipping of the mutated dystrophin pre-mRNAs, reading through termination codons with small molecules that mask premature stop codons, dystrophin gene repair by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated genetic engineering, and increasing
utrophin levels. Our analyses highlight the importance of various dystrophin and
utrophin domains in Duchenne muscular dystrophy treatment, providing insights into designing novel therapeutic compounds with improved efficacy and decreased immunoreactivity. While the necessary actin and β-dystroglycan binding sites are present in both proteins, important functional distinctions can be identified in these domains and some other parts of truncated dystrophins might need redesigning due to their potentially immunogenic qualities. Alternatively, therapies based on utrophins might provide a safer and more effective approach.