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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Turk, Boris / Wittinghofer, Alfred

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

Jiaxin Hu1 / Keith T. Gagnon1 / Jing Liu1 / Jonathan K. Watts1 / Jeja Syeda-Nawaz1 / C. Frank Bennett2 / Eric E. Swayze2 / John Randolph3 / Jyoti Chattopadhyaya4 / 1

1Departments of Pharmacology and Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390-9041, USA

2Isis Pharmaceuticals, 1896 Rutherford Road, Carlsbad, CA 92008, USA

3Glen Research Corporation, 22825 Davis Drive, Sterling, VA 20164, USA

4Department of Bioorganic Chemistry, Uppsala University, Biomedical Center, Box 581, S-751 23 Uppsala, Sweden

Corresponding author

Citation Information: Biological Chemistry. Volume 392, Issue 4, Pages 315–325, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: 10.1515/bc.2011.045, July 2011

Publication History

Published Online:


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.

Keywords: allele-selective; ataxin-3; peptide nucleic acid; siRNA; spinocerebellar ataxia-3

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