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Abstract
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.
Highlights
DNAzymes (Dzs) are single-stranded RNA-cleaving DNAs that typically consist of a catalytic core and two flanking RNA-binding arms for target recognition
Polyglutamine diseases are a group of incurable neurodegenerative disorders caused by CAG repeat expansion in coding regions, including Huntington’s disease (HD), spinocerebellar ataxias (SCA types 1, 2, 3, 6, 7, and 17), dentatorubropallidoluysian atrophy (DRPLA), and spinobulbar muscular atrophy (SBMA) [3]
Our data provide the proof of principle that DNAzyme cleaves expanded CAG repeats of multiple polyQ diseases
Summary
DNAzymes (Dzs) are single-stranded RNA-cleaving DNAs that typically consist of a catalytic core and two flanking RNA-binding arms for target recognition. The. 15-nucleotide (nt) core has been independently isolated under different cation selections such as Mg2+, Mn2+, Ca2+, Zn2+, and Pb2+ and shown to twist into a pseudoknot with the two RNA binding arms 70° apart in the crystal structure [2]. 15-nucleotide (nt) core has been independently isolated under different cation selections such as Mg2+, Mn2+, Ca2+, Zn2+, and Pb2+ and shown to twist into a pseudoknot with the two RNA binding arms 70° apart in the crystal structure [2] Despite their high reprogrammability and versatility for chemical modification and nanoconjugation, the theranostic value and means of delivery are largely unexplored. Ridding cells of the mutant polyQ RNA/protein has become a major disease intervention and its success is thought to ameliorate any downstream pathomechanistic defects
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