Cas9 editing of ATXN1 in a spinocerebellar ataxia type 1 mice and human iPSC-derived neurons

IF 6.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Molecular Therapy. Nucleic Acids Pub Date : 2024-08-31 DOI:10.1016/j.omtn.2024.102317

Kelly J. Fagan, Guillem Chillon, Ellie M. Carrell, Elisa A. Waxman, Beverly L. Davidson

引用次数: 0

Abstract

Spinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disease caused by an expansion of the CAG repeat region of the gene. Currently there are no disease-modifying treatments; however, previous work has shown the potential of gene therapy, specifically RNAi, as a potential modality. Cas9 editing offers potential for these patients but has yet to be evaluated in SCA1 models. To test this, we first characterized the number of transgenes harbored in the common B05 mouse model of SCA1. Despite having five copies of the human mutant transgene, a 20% reduction of improved behavior deficits without increases in inflammatory markers. Importantly, the editing approach was confirmed in induced pluripotent stem cell (iPSC) neurons derived from patients with SCA1, promoting the translatability of the approach to patients.

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在脊髓小脑共济失调 1 型小鼠和人类 iPSC 衍生神经元中对 ATXN1 进行 Cas9 编辑

脊髓小脑共济失调 1 型（SCA1）是一种成人发病型神经退行性疾病，由基因 CAG 重复区扩增引起。目前还没有改变疾病的治疗方法；不过，先前的研究表明，基因疗法（特别是 RNAi）是一种潜在的治疗方式。Cas9 编辑为这些患者提供了治疗潜力，但尚未在 SCA1 模型中进行评估。为了验证这一点，我们首先鉴定了常见的 B05 SCA1 小鼠模型中携带的转基因数量。尽管有五个拷贝的人类突变转基因，但行为障碍的改善减少了 20%，而炎症标记物却没有增加。重要的是，编辑方法在来自SCA1患者的诱导多能干细胞（iPSC）神经元中得到了证实，促进了该方法对患者的可转化性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Therapy. Nucleic Acids MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

15.40

自引率

1.10%

发文量

336

审稿时长

20 weeks

期刊介绍： Molecular Therapy Nucleic Acids is an international, open-access journal that publishes high-quality research in nucleic-acid-based therapeutics to treat and correct genetic and acquired diseases. It is the official journal of the American Society of Gene & Cell Therapy and is built upon the success of Molecular Therapy. The journal focuses on gene- and oligonucleotide-based therapies and publishes peer-reviewed research, reviews, and commentaries. Its impact factor for 2022 is 8.8. The subject areas covered include the development of therapeutics based on nucleic acids and their derivatives, vector development for RNA-based therapeutics delivery, utilization of gene-modifying agents like Zn finger nucleases and triplex-forming oligonucleotides, pre-clinical target validation, safety and efficacy studies, and clinical trials.