Combination Treatment of Erythromycin and Furamidine Provides Additive and Synergistic Rescue of Mis-splicing in Myotonic Dystrophy Type 1 Models,ACS Pharmacology & Translational Science

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Combination Treatment of Erythromycin and Furamidine Provides Additive and Synergistic Rescue of Mis-splicing in Myotonic Dystrophy Type 1 Models
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2019-07-23 , DOI: 10.1021/acsptsci.9b00020
Jana R Jenquin ₁ , Hongfen Yang ₂ , Robert W Huigens ₂ , Masayuki Nakamori ₃ , J Andrew Berglund _{1,

4}

Affiliation

Myotonic dystrophy type 1 (DM1) is a multisystemic disease that presents with clinical symptoms including myotonia, cardiac dysfunction, and cognitive impairment. DM1 is caused by a CTG expansion in the 3′ UTR of the DMPK gene. The transcribed expanded CUG-repeat RNA sequester the muscleblind-like (MBNL) and up-regulate the CUG-BP Elav-like (CELF) families of RNA-binding proteins leading to global mis-regulation of RNA processing and altered gene expression. Currently, there are no disease-targeting treatments for DM1. Given the multistep pathogenic mechanism, combination therapies targeting multiple aspects of the disease mechanism may be a viable therapeutic approach. Here, as proof-of-concept, we studied a combination of two previously characterized small molecules, erythromycin and furamidine, in two DM1 models. In DM1 patient-derived myotubes, the rescue of mis-splicing was observed with little to no cell toxicity. In a DM1 mouse model, a combination of erythromycin and the prodrug of furamidine (pafuramidine), administered orally, displayed both additive and synergistic mis-splicing rescue. Gene expression was only modestly affected, and over 40% of the genes showing significant expression changes were rescued back toward WT expression levels. Further, the combination treatment partially rescued the myotonia phenotype in the DM1 mouse. This combination treatment showed a high degree of mis-splicing rescue coupled with low off-target gene expression changes. These results indicate that combination therapies are a promising therapeutic approach for DM1.

中文翻译：

红霉素和呋喃胺的联合治疗为强直性营养不良 1 型模型中的错误剪接提供了相加和协同的补救措施

1 型强直性肌营养不良症 (DM1) 是一种多系统疾病，其临床症状包括肌强直、心脏功能障碍和认知障碍。DM1 是由DMPK的 3'UTR 中的 CTG 扩展引起的基因。转录的扩展 CUG 重复 RNA 隔离肌盲样 (MBNL) 并上调 RNA 结合蛋白的 CUG-BP Elav 样 (CELF) 家族，导致 RNA 加工的全局错误调节和基因表达改变。目前，没有针对 DM1 的疾病靶向治疗。鉴于多步骤致病机制，针对疾病机制多个方面的联合疗法可能是一种可行的治疗方法。在这里，作为概念验证，我们在两个 DM1 模型中研究了两种先前表征的小分子红霉素和呋喃脒的组合。在 DM1 患者衍生的肌管中，观察到错误剪接的挽救几乎没有细胞毒性。在 DM1 小鼠模型中，口服红霉素和呋喃脒前药 (pafuramidine) 的组合，显示了加性和协同错误拼接救援。基因表达仅受到轻微影响，超过 40% 的表现出显着表达变化的基因被恢复到 WT 表达水平。此外，联合治疗部分挽救了 DM1 小鼠的肌强直表型。这种组合治疗显示出高度的错误剪接拯救以及低的脱靶基因表达变化。这些结果表明，联合疗法是一种有前途的 DM1 治疗方法。这种组合治疗显示出高度的错误剪接拯救以及低的脱靶基因表达变化。这些结果表明，联合疗法是一种有前途的 DM1 治疗方法。这种组合治疗显示出高度的错误剪接拯救以及低的脱靶基因表达变化。这些结果表明，联合疗法是一种有前途的 DM1 治疗方法。

更新日期：2019-07-23

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