德国马克斯·普朗克心肺研究所的Didier Y. R. Stainier课题组在研究中取得进展。他们的研究发现转录适应在杜氏肌营养不良中上调营养蛋白。这一研究成果发表在2025年2月12日出版的国际学术期刊《自然》上。

为了进一步研究这种UTRN上调，研究组首先通过在其可选剪接的外显子之一中引入过早终止密码子（PTC），开发了DMD的诱导信使RNA （mRNA）降解系统。PTC-外显子的内含触发DMD突变体mRNA衰变和UTRN上调。值得注意的是，阻断无义介导的mRNA衰减会导致UTRN上调的逆转，而过表达DMD则不会。

此外，在野生型细胞中过表达DMD^PTC小基因会导致UTRN上调，含有自切割核酶的野生型DMD小基因也是如此。为了将这些发现置于治疗背景下，研究小组将剪接开关反义寡核苷酸（ASOs）用于诱导DMD外框外显子的跳跃，旨在引入PTC。研究小组发现这些ASOs与UTRN上调有关。此外，当使用ASO来恢复来自DMD^ΔE52患者的肌管的DMD阅读框架时，UTRN上调被降低。总之，这些结果表明，一种基于mRNA衰变的转录适应机制在DMD^PTC患者的UTRN上调中起着关键作用，并且它们突出了ASOs和核酶在通过转录适应诱导遗传补偿方面尚未被探索的治疗应用。

据悉，杜氏细胞营养不良症（DMD）是一种由编码肌营养不良蛋白的DMD基因突变引起的细胞退行性疾病。肌营养蛋白（UTRN）是DMD的遗传和功能同源蛋白，在一些DMD患者中表达上调。

附：英文原文

Title: Transcriptional adaptation upregulates utrophin in Duchenne muscular dystrophy

Author: Falcucci, Lara, Dooley, Christopher M., Adamoski, Douglas, Juan, Thomas, Martinez, Justin, Georgieva, Angelina M., Mamchaoui, Kamel, Cirzi, Cansu, Stainier, Didier Y. R.

Issue&Volume: 2025-02-12

Abstract: Duchenne muscular dystrophy (DMD) is a muscle-degenerating disease caused by mutations in the DMD gene, which encodes the dystrophin protein1,2. Utrophin (UTRN), the genetic and functional paralogue of DMD, is upregulated in some DMD patients3,4,5. To further investigate this UTRN upregulation, we first developed an inducible messenger RNA (mRNA) degradation system for DMD by introducing a premature termination codon (PTC) in one of its alternatively spliced exons. Inclusion of the PTC-containing exon triggers DMD mutant mRNA decay and UTRN upregulation. Notably, blocking nonsense-mediated mRNA decay results in the reversal of UTRN upregulation, whereas overexpressing DMD does not. Furthermore, overexpressing DMD^PTC minigenes in wild-type cells causes UTRN upregulation, as does a wild-type DMD minigene containing a self-cleaving ribozyme. To place these findings in a therapeutic context, we used splice-switching antisense oligonucleotides (ASOs) to induce the skipping of out-of-frame exons of DMD, aiming to introduce PTCs. We found that these ASOs cause UTRN upregulation. In addition, when using an ASO to restore the DMD reading frame in myotubes derived from a DMD^ΔE52 patient, an actual DMD treatment, UTRN upregulation was reduced. Altogether, these results indicate that an mRNA decay-based mechanism called transcriptional adaptation6,7,8 plays a key role in UTRN upregulation in DMD^PTC patients, and they highlight an unexplored therapeutic application of ASOs, as well as ribozymes, in inducing genetic compensation via transcriptional adaptation.

DOI: 10.1038/s41586-024-08539-x

Source: https://www.nature.com/articles/s41586-024-08539-x