在亨廷顿氏病的 HTT 降低策略背景下重新审视成人野生型 Htt 失活的结果

Sara Regio, Gabriel Vachey, Enrique Goñi, Fábio Duarte, Margareta Rybarikova, Mélanie Sipion, Maria Rey, Maite Huarte, N. Déglon
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摘要

降低亨廷顿蛋白的策略是亨廷顿舞蹈病治疗方法的核心。最近的研究报道了通过条件敲除亨廷顿蛋白诱导年龄和细胞类型特异性表型,但这些实验条件并没有精确地模仿亨廷顿蛋白降低或基因编辑条件,就靶细胞和大脑分布而言,也没有提供转录谱。在这里,我们使用CNS基因治疗项目中常用的腺相关传递系统和自我失活的KamiCas9基因编辑系统来研究野生型小鼠亨廷顿蛋白失活在成年神经元中的长期后果,从而研究亨廷顿蛋白失活在这些细胞中的可行性和安全性。行为和神经病理学分析以及单核RNA测序表明,成年小鼠77%纹状体神经元和16%皮质突起神经元的亨廷顿蛋白编辑不会引起行为缺陷或细胞毒性。在11.5个月大的动物中进行的单核RNA测序显示,亨廷顿蛋白失活不会改变纹状细胞的轮廓或比例。很少有差异表达的基因被鉴定出来,Augur分析证实,在所有细胞类型中,对亨廷顿蛋白失活的反应非常有限。因此,我们的研究结果表明,成人纹状体和投射神经元的野生型亨廷顿蛋白失活是长期耐受的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Revisiting the outcome of adult wild-type Htt inactivation in the context of HTT-lowering strategies for Huntington’s disease
Huntingtin-lowering strategies are central to therapeutic approaches for Huntington's disease. Recent studies reported the induction of age- and cell type-specific phenotypes by conditional huntingtin knockout, but these experimental conditions did not precisely mimic huntingtin-lowering or gene-editing conditions in terms of the cells targeted and brain distribution, and no transcriptional profiles were provided. Here, we used the adeno-associated delivery system commonly used in CNS gene therapy programs and the self-inactivating KamiCas9 gene-editing system to investigate the long-term consequences of wild-type mouse huntingtin inactivation in adult neurons and, thus, the feasibility and safety of huntingtin inactivation in these cells. Behavioral and neuropathological analyses and single-nuclei RNA sequencing indicated that huntingtin editing in 77% of striatal neurons and 16% of cortical projecting neurons in adult mice induced no behavioral deficits or cellular toxicity. Single-nuclei RNA sequencing in 11.5-month-old animals showed that huntingtin inactivation did not alter striatal-cell profiles or proportions. Few differentially expressed genes were identified and Augur analysis confirmed an extremely limited response to huntingtin inactivation in all cell types. Our results therefore indicate that wild-type huntingtin inactivation in adult striatal and projection neurons is well tolerated in the long term.
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