Silencing of genes responsible for polyQ diseases using chemically modified single-stranded siRNAs

  • Agnieszka Fiszer Department of Molecular Biomedicine Institute of Bioorganic Chemistry Polish Academy of Sciences Z. Noskowskiego str. 12/14 61-704 Poznan
  • Marianna E Ellison-Klimontowicz
  • Wlodzimierz J Krzyzosiak Department of Molecular Biomedicine Institute of Bioorganic Chemistry Polish Academy of Sciences Z. Noskowskiego str. 12/14 61-704 Poznan
Keywords: siRNA, CAG repeats, polyglutamine diseases, Huntington’s disease


Polyglutamine (polyQ) diseases comprise a group of nine genetic disorders that are caused by the expansion of the CAG triplet repeat, which encodes glutamine, in unrelated single genes. The pathogenesis is caused by the disruption of cellular pathways by the expression products of the mutant gene, i.e., proteins containing polyQ tracts and mutant transcripts. In considering oligonucleotide (ON)-based therapeutic approaches for polyQ diseases, the very attractive CAG repeat-targeting strategy offers selective silencing of the mutant allele by directly targeting the mutation site. CAG repeat-targeting miRNA-like siRNAs have been shown to specifically inhibit mutant gene expression, and their characteristic feature is the formation of mismatches in their interactions with the target site. 

Here, we designed novel single-stranded siRNAs that contain base substitutions and chemical modifications and tested these oligonucleotides in cellular models of Huntington’s disease (HD), spinocerebellar ataxia type 3 (SCA3) and dentatorubral-pallidoluysian atrophy (DRPLA), including HD mouse striatal cells. Selected siRNAs caused the efficient and selective downregulation of the mutant protein levels.


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