DNAzyme Cleavage of CAG Repeat RNA in Polyglutamine Diseases

Elsevier BV - Tập 18 - Trang 1710-1728 - 2021
Nan Zhang1, Brittani Bewick1, Jason Schultz1, Anjana Tiwari1, Robert Krencik2, Aijun Zhang3, Kaho Adachi4, Guangbin Xia5, Kyuson Yun1, Partha Sarkar6, Tetsuo Ashizawa1
1Department of Neurology, Neuroscience Program, Houston Methodist Research Institute, Houston, USA
2Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research Institute, Houston, USA
3Center for Bioenergetics, Department of Neurosurgery, Houston Methodist Research Institute, Houston, USA
4Department of Molecular and Cell Biology, UC-Berkeley, Berkeley, USA
5Indiana University School of Medicine-Fort Wayne, Fort Wayne, USA
6Department of Neurology and Department of Neuroscience, Cell Biology and Anatomy, UTMB Health, Galveston, USA

Tóm tắt

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.

Tài liệu tham khảo

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