DNAzyme Cleavage of CAG Repeat RNA in Polyglutamine Diseases

Nan Zhang; Brittani Bewick; Jason Schultz; Anjana Tiwari; Robert Krencik; Aijun Zhang; Kaho Adachi; Guangbin Xia; Kyuson Yun; Partha Sarkar; Tetsuo Ashizawa

doi:10.1007/s13311-021-01075-w

DNAzyme Cleavage of CAG Repeat RNA in Polyglutamine Diseases

Nan Zhang, Brittani Bewick, Jason Schultz, Anjana Tiwari, Robert Krencik, Aijun Zhang, Kaho Adachi, Guangbin Xia, Kyuson Yun, Partha Sarkar, Tetsuo Ashizawa

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1710-1728
Number of pages	19
Journal	Neurotherapeutics
Volume	18
Issue number	3
DOIs	https://doi.org/10.1007/s13311-021-01075-w
State	Published - Jul 2021

Keywords

CAG repeats
DNAzyme
Huntington’s disease
Microsatellite expansion
Polyglutamine
Spinocerebellar ataxia

ASJC Scopus subject areas

Pharmacology
Clinical Neurology
Pharmacology (medical)

Divisions

Endocrinology, Diabetes and Metabolism

Access to Document

10.1007/s13311-021-01075-w

Cite this

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title = "DNAzyme Cleavage of CAG Repeat RNA in Polyglutamine Diseases",

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.",

keywords = "CAG repeats, DNAzyme, Huntington{\textquoteright}s disease, Microsatellite expansion, Polyglutamine, Spinocerebellar ataxia",

author = "Nan Zhang and Brittani Bewick and Jason Schultz and Anjana Tiwari and Robert Krencik and Aijun Zhang and Kaho Adachi and Guangbin Xia and Kyuson Yun and Partha Sarkar and Tetsuo Ashizawa",

note = "Funding Information: This work was supported by a National Ataxia Foundation Young Investigator-SCA Award (\#93000) to N.Z., a Foster Research Fund to T.A., National Institute on Aging of the National Institutes of Health grant (R21AG064567) to R.K., and the National Institutes of Health grants (RO1 NSO79541-01 and R01 EY026089-01A1) to P.S.S. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = jul,

doi = "10.1007/s13311-021-01075-w",

language = "English (US)",

volume = "18",

pages = "1710--1728",

journal = "Neurotherapeutics",

issn = "1933-7213",

publisher = "Elsevier B.V.",

number = "3",

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TY - JOUR

T1 - DNAzyme Cleavage of CAG Repeat RNA in Polyglutamine Diseases

AU - Zhang, Nan

AU - Bewick, Brittani

AU - Schultz, Jason

AU - Tiwari, Anjana

AU - Krencik, Robert

AU - Zhang, Aijun

AU - Adachi, Kaho

AU - Xia, Guangbin

AU - Yun, Kyuson

AU - Sarkar, Partha

AU - Ashizawa, Tetsuo

N1 - Funding Information: This work was supported by a National Ataxia Foundation Young Investigator-SCA Award (#93000) to N.Z., a Foster Research Fund to T.A., National Institute on Aging of the National Institutes of Health grant (R21AG064567) to R.K., and the National Institutes of Health grants (RO1 NSO79541-01 and R01 EY026089-01A1) to P.S.S. Publisher Copyright: © 2021, The Author(s).

PY - 2021/7

Y1 - 2021/7

N2 - 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.

AB - 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.

KW - CAG repeats

KW - DNAzyme

KW - Huntington’s disease

KW - Microsatellite expansion

KW - Polyglutamine

KW - Spinocerebellar ataxia

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ER -

DNAzyme Cleavage of CAG Repeat RNA in Polyglutamine Diseases

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