Allele-selective inhibition of ataxin-3 (ATX3) expression by antisense oligomers and duplex RNAs
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Jiaxin Hu
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.
©2011 by Walter de Gruyter Berlin New York
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Artikel in diesem Heft
- Guest Editorial
- Highlight: Mechanisms of RNA-mediated regulation
- HIGHLIGHT: 62ND MOSBACH COLLOQUIUM OF THE GBM ‘MECHANISMS OF RNA-MEDIATED REGULATION’
- Clustered regularly interspaced short palindromic repeats (CRISPRs): the hallmark of an ingenious antiviral defense mechanism in prokaryotes
- Regulatory RNAs in cyanobacteria: developmental decisions, stress responses and a plethora of chromosomally encoded cis-antisense RNAs
- RNA-dependent RNA polymerases in RNA silencing
- Traces of post-transcriptional RNA modifications in deep sequencing data
- Allele-selective inhibition of ataxin-3 (ATX3) expression by antisense oligomers and duplex RNAs
- PROTEIN STRUCTURE AND FUNCTION
- The effects of a plant proteinase inhibitor from Enterolobium contortisiliquum on human tumor cell lines
- Role of unique basic residues in cytotoxic, antibacterial and antiparasitic activities of human eosinophil cationic protein
- Antiangiogenic kringles derived from human plasminogen and apolipoprotein(a) inhibit fibrinolysis through a mechanism that requires a functional lysine-binding site
- Changing nucleotide specificity of the DEAD-box helicase Hera abrogates communication between the Q-motif and the P-loop
- Identification of plasma haptoglobin forms which loosely bind hemoglobin
- MOLECULAR MEDICINE
- Organelle stress-induced activating transcription factor-3 downregulates low-density lipoprotein receptor expression in Sk-Hep1 human liver cells
- CELL BIOLOGY AND SIGNALING
- Helicobacter pylori-induced tyrosine phosphorylation of IKKβ contributes to NF-κB activation
