在阿舍尔综合征1F型的人性化小鼠模型中,通过腺基编辑挽救听力

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Cole W Peters¹, Killian S Hanlon², Maryna V Ivanchenko¹

¹Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.

Molecular therapy : the journal of the American Society of Gene Therapy

|June 14, 2023

概括

使用腺基编辑器 (ABE) 的基因疗法对阿舍尔综合征1F型 (USH1F) 有望. 这种方法在小鼠模型中成功纠正了PCDH15基因突变,在某些情况下恢复了听力.

科学领域:

遗传学是一个遗传学.
分子生物学分子生物学
眼科医生眼科眼科

背景情况:

艾舍氏综合征1F型 (USH1F) 是一种遗传性疾病,导致先天性听力和平衡丧失,以及渐进的视力障碍.
USH1F通常是由PCDH15基因的突变引起的,在阿什基纳兹人群中普遍存在特定的C→T突变 (R245X).

研究的目的:

评估腺基编辑器 (ABE) 在纠正PCDH15基因R245X突变中的有效性.
开发和测试一种基因编辑策略,用于使用人性化的小鼠模型治疗USH1F.

主要方法:

为USH1F.开发了一个人性化的PCdh15^R245X鼠标模型.
通过双腺相关病毒 (AAV) 载体向新生儿USH1F小鼠的耳输送了分裂的ABE.
向构成式无效和晚期删除条件的Pcdh15淘汰赛小鼠模型中使用了ABE载体.

主要成果:

ABE成功地逆转了PCDH15基因中的R245X突变,恢复了其序列和功能.
在构造性零小鼠中,听力没有恢复,这可能是由于早期的耳毛细胞失调.
在ABE矢量注射后的晚期删除条件Pcdh15淘汰模式中,听力得到了拯救.

结论:

腺基编辑可以纠正尾中的PCDH15 R245X突变.
这项研究证明了ABE在治疗USH1F和恢复听力方面的潜力,特别是在发生重大耳损伤之前应用时.

关键词:

在 AAV AAV AAV 中.在PCDH15中.阿舍尔综合征是什么意思阿舍尔综合征是什么意思基础编辑器基础编辑器失明失明失明失明甲状腺 (cochlea) 是一种听力障碍听力障碍听力障碍基因编辑基因编辑基因治疗的基因疗法头发细胞是指毛细胞.

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