Human Translational Genomics Group. University Research Institute for Biotechnology and Biomedicine (BIOTECMED), Universidad de Valencia, 46100 Burjassot, Valencia, Spain.
INCLIVA Biomedical Research Institute, Avenue Menéndez Pelayo 4 acc, 46010 Valencia, Spain.
Sci Adv. 2024 Oct 11;10(41):eadn6525. doi: 10.1126/sciadv.adn6525. Epub 2024 Oct 9.
This study evaluated therapeutic antimiRs in primary myoblasts from patients with myotonic dystrophy type 1 (DM1). DM1 results from unstable CTG repeat expansions in the gene, leading to variable clinical manifestations by depleting muscleblind-like splicing regulator protein MBNL1. AntimiRs targeting natural repressors miR-23b and miR-218 boost MBNL1 expression but must be optimized for a better pharmacological profile in humans. In untreated cells, miR-23b and miR-218 were up-regulated, which correlated with CTG repeat size, supporting that active MBNL1 protein repression synergizes with the sequestration by CUG expansions in . AntimiR treatment improved RNA toxicity readouts and corrected regulated exon inclusions and myoblast defects such as fusion index and myotube area across CTG expansions. Unexpectedly, the treatment also reduced transcripts and ribonuclear foci. A leading antimiR reversed 68% of dysregulated genes. This study highlights the potential of antimiRs to treat various DM1 forms across a range of repeat sizes and genetic backgrounds by mitigating MBNL1 sequestration and enhancing protein synthesis.
本研究评估了肌强直性营养不良 1 型（DM1）患者原代成肌细胞中的治疗性抗微小 RNA（antimiRs）。DM1 是由于基因中的不稳定 CTG 重复扩展，导致肌肉盲样剪接调节蛋白 MBNL1 耗竭，从而导致临床表现的多变。针对天然抑制物 miR-23b 和 miR-218 的 antimiRs 可提高 MBNL1 的表达，但必须在人类中进行优化，以获得更好的药理学特征。在未经处理的细胞中，miR-23b 和 miR-218 上调，这与 CTG 重复大小相关，表明活跃的 MBNL1 蛋白抑制与 CUG 扩展在 中的隔离协同作用。antimiR 治疗可改善 RNA 毒性指标，并纠正调节外显子包含和成肌细胞缺陷，如融合指数和肌管面积，跨越 CTG 扩展。出乎意料的是，该治疗还降低了 转录物和核糖核蛋白焦点。一种领先的 antimiR 逆转了 68%的失调基因。这项研究强调了 antimiRs 通过减轻 MBNL1 隔离和增强蛋白质合成，治疗各种 DM1 形式的潜力，跨越一系列重复大小和遗传背景。
