评估基因替代策略治疗MTRFR缺乏症的可行性。

IF 3.3 3区 医学 Q2 CELL BIOLOGY
Disease Models & Mechanisms Pub Date : 2025-05-01 Epub Date: 2025-06-02 DOI:10.1242/dmm.052120
Samia L Pratt, Mariana Zarate-Mendez, Lidiia Koludarova, Sonja Jansson, Mikko Airavaara, Irena Hlushchuk, David Coleman, Caleb Heffner, Rita Horvath, Brendan J Battersby, Robert W Burgess
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引用次数: 0

摘要

线粒体翻译释放因子(MTRFR)在蛋白质合成中催化一个终止步骤,促进新生链从线粒体体中释放。MTRFR的致病性变异导致MTRFR缺乏,是功能丧失变异。在这里,我们测试了基因替代作为一种可能的治疗策略。在小鼠中产生截断突变(K155*);然而,纯合子在胚胎期死亡,而该K155*等位基因的杂合小鼠是正常的。我们还产生了表达野生型人类MTRFR或部分功能MTRFR的转基因菌株。尽管在体外过度表达会产生剂量依赖性表型,但这两种转基因在体内都不会产生不良反应。在K155*纯合子小鼠中,野生型MTRFR转基因完全拯救了表型,只有一个拷贝存在,而突变型转基因拯救的效率较低。用野生型MTRFR转基因拯救的小鼠的详细评估显示没有异常。在人诱导多能干细胞(hiPSC)衍生的敲低神经元中,通过aav9介导的MTRFR递送来纠正线粒体表型。因此,我们在体内没有发现截断基因产物或过表达MTRFR的毒性,并且MTRFR的表达在小鼠和hiPSC模型中都纠正了表型。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Evaluating the feasibility of gene replacement strategies to treat MTRFR deficiency.

Mitochondrial translation release factor in rescue (MTRFR) catalyzes a termination step in protein synthesis, facilitating release of the nascent chain from mitoribosomes. Pathogenic variants in MTRFR cause MTRFR deficiency and are loss-of-function variants. Here, we tested gene replacement as a possible therapeutic strategy. A truncating mutation (K155*) was generated in mice; however, homozygotes die embryonically whereas mice heterozygous for this K155* allele are normal. We also generated transgenic strains expressing either wild-type human MTRFR or a partially functional MTRFR. Despite dose-dependent phenotypes from overexpression in vitro, neither transgene caused adverse effects in vivo. In K155* homozygous mice, the wild-type MTRFR transgene completely rescued the phenotype with only one copy present, whereas the mutant transgene rescued less efficiently. Detailed evaluation of mice rescued with the wild-type MTRFR transgene revealed no abnormalities. In human induced pluripotent stem cell (hiPSC)-derived knockdown neurons, mitochondrial phenotypes were corrected by AAV9-mediated delivery of MTRFR. Thus, we find no toxicity from truncated gene products or overexpression of MTRFR in vivo, and expression of MTRFR corrects phenotypes in both mouse and hiPSC models.

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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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