Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter July 25, 2011

Allele-selective inhibition of ataxin-3 (ATX3) expression by antisense oligomers and duplex RNAs

  • Jiaxin Hu , Keith T. Gagnon , Jing Liu , Jonathan K. Watts , Jeja Syeda-Nawaz , C. Frank Bennett , Eric E. Swayze , John Randolph , Jyoti Chattopadhyaya and David R. Corey EMAIL logo
From the journal Biological Chemistry

Abstract

Spinocerebellar ataxia-3 (also known as Machado-Joseph disease) is an incurable neurodegenerative disorder caused by expression of a mutant variant of ataxin-3 (ATX3) protein. Inhibiting expression of ATX3 would provide a therapeutic strategy, but indiscriminant inhibition of both wild-type and mutant ATX3 might lead to undesirable side effects. An ideal silencing agent would block expression of mutant ATX3 while leaving expression of wild-type ATX3 intact. We have previously observed that peptide nucleic acid (PNA) conjugates targeting the expanded CAG repeat within ATX3 mRNA block expression of both alleles. We have now identified additional PNAs capable of inhibiting ATX3 expression that vary in length and in the nature of the conjugated cation chain. We can also achieve potent and selective inhibition using duplex RNAs containing one or more mismatches relative to the CAG repeat. Anti-CAG antisense bridged nucleic acid oligonucleotides that lack a cationic domain are potent inhibitors but are not allele-selective. Allele-selective inhibitors of ATX3 expression provide insights into the mechanism of selectivity and promising lead compounds for further development and in vivo investigation.


Corresponding author

Received: 2010-11-17
Accepted: 2011-1-7
Published Online: 2011-07-25
Published in Print: 2011-04-01

©2011 by Walter de Gruyter Berlin New York

Downloaded on 29.3.2024 from https://www.degruyter.com/document/doi/10.1515/bc.2011.045/html
Scroll to top button