Correcting a patient-specific Rhodopsin mutation with adenine base editor in a mouse model.

IF 12.1 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Xiaoxue He, Tong Yan, Zongming Song, Lue Xiang, Jiayang Xiang, Yeqin Yang, Kaiqun Ren, Jicheng Bu, Xilin Xu, Zhuo Li, Xiaowei Guo, Bin Lin, Qinghua Zhou, Ge Lin, Feng Gu
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Abstract

Genome editing offers a great promise to treating human genetic diseases. To assess genome-editing-mediated therapeutic effects in vivo, an animal model is indispensable. The genomic disparities between mice and humans often impede the direct clinical application of genome-editing-mediated treatments using conventional mouse models. Thus, the generation of a mouse model with a humanized genomic segment containing a patient-specific mutation is highly sought after for translational research. In this study, we successfully developed a knockin mouse model for autosomal-dominant retinitis pigmentosa (adRP), designated as hT17M knockin, which incorporates a 75-nucleotide DNA segment with the T17M mutation (Rhodopsin-c.C50T; p.T17M). This model demonstrated significant reductions in electroretinogram amplitudes and exhibited disruptions in retinal structure. Subsequently, we administered an adeno-associated virus vectors carrying an adenine base editor (ABE) and a single-guide RNA specifically targeting the T17M mutation, achieving a peak correction rate of 39.7% at the RNA level and significantly improving retinal function in ABE-injected mice. These findings underscore that the hT17M knockin mouse model recapitulates the clinical features of adRP patients and exhibits therapeutic effects with ABE-mediated treatments. It offers a promising avenue for the development of gene-editing therapies for RP.

用腺嘌呤碱基编辑器在小鼠模型中纠正患者特异性视紫红质突变。
基因组编辑为治疗人类遗传疾病提供了巨大的希望。为了评估基因组编辑介导的体内治疗效果,动物模型是必不可少的。然而,小鼠和人类之间的基因组差异往往阻碍了使用传统小鼠模型进行基因组编辑介导治疗的直接临床应用。因此,具有包含患者特异性突变的人源化基因组片段的小鼠模型的产生在转化研究中受到高度追捧。在本研究中,我们成功建立了常染色体显性视网膜色素变性(adRP)的敲入小鼠模型,命名为hT17M敲入,该敲入包含75个核苷酸的DNA片段与T17M突变(rhodopsinc . c50t;p.T17M)。该模型显示视网膜电图(ERG)振幅显著降低,并表现出视网膜结构破坏。随后,我们使用了一种携带腺嘌呤碱基编辑器(ABE)和一种特异性靶向T17M突变的单导RNA (sgRNA)的腺相关病毒(aav),在RNA水平上达到了39.7%的峰值校正率,并显著改善了注射ABE的小鼠的视网膜功能。这些发现强调hT17M敲入小鼠模型概括了adRP患者的临床特征,并显示出abe介导治疗的治疗效果。它为视网膜色素变性基因编辑疗法的发展提供了一条有希望的途径。
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来源期刊
Molecular Therapy
Molecular Therapy 医学-生物工程与应用微生物
CiteScore
19.20
自引率
3.20%
发文量
357
审稿时长
3 months
期刊介绍: Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.
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