Department of Neurology, Neuroscience Program, Houston Methodist Research Institute, Houston, TX, USA.
Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA.
Neurotherapeutics. 2021 Jul;18(3):1710-1728. doi: 10.1007/s13311-021-01075-w. Epub 2021 Jun 23.
CAG repeat expansion is the genetic cause of nine incurable polyglutamine (polyQ) diseases with neurodegenerative features. Silencing repeat RNA holds great therapeutic value. Here, we developed a repeat-based RNA-cleaving DNAzyme that catalyzes the destruction of expanded CAG repeat RNA of six polyQ diseases with high potency. DNAzyme preferentially cleaved the expanded allele in spinocerebellar ataxia type 1 (SCA1) cells. While cleavage was non-allele-specific for spinocerebellar ataxia type 3 (SCA3) cells, treatment of DNAzyme leads to improved cell viability without affecting mitochondrial metabolism or p62-dependent aggresome formation. DNAzyme appears to be stable in mouse brain for at least 1 month, and an intermediate dosage of DNAzyme in a SCA3 mouse model leads to a significant reduction of high molecular weight ATXN3 proteins. Our data suggest that DNAzyme is an effective RNA silencing molecule for potential treatment of multiple polyQ diseases.
CAG 重复扩展是导致具有神经退行性特征的九种无法治愈的多聚谷氨酰胺（polyQ）疾病的遗传原因。沉默重复 RNA 具有很大的治疗价值。在这里，我们开发了一种基于重复的 RNA 切割 DNA 酶，该酶能高效催化六种 polyQ 疾病中扩增的 CAG 重复 RNA 的破坏。DNA 酶优先切割脊髓小脑共济失调症 1 型（SCA1）细胞中的扩增等位基因。虽然 DNA 酶对脊髓小脑共济失调症 3 型（SCA3）细胞的切割是非等位基因特异性的，但 DNA 酶的处理导致细胞活力提高，而不影响线粒体代谢或 p62 依赖性聚集体形成。DNA 酶在小鼠大脑中至少稳定 1 个月，并且 SCA3 小鼠模型中的中等剂量 DNA 酶可显著降低高分子量 ATXN3 蛋白。我们的数据表明，DNA 酶是一种有效的 RNA 沉默分子，可用于治疗多种 polyQ 疾病。
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