Allele-Selective Inhibition of Mutant Huntingtin with 2-Thio- and C5-Triazolylphenyl-Deoxythymidine-Modified Antisense Oligonucleotides

作者：Ostergaard Michael E; Kumar Pawan; Nichols Josh; Watt Andrew; Sharma Pawan K; Nielsen Poul; Seth Punit P^*

来源：Nucleic Acid Therapeutics, 2015, 25(5): 266-274.

DOI：10.1089/nat.2015.0547

We report the effect of introducing a single incorporation of 2-thio-deoxythymidine (2S-dT) or C5-Triazolylphenyl-deoxythymidine (5-TrPh-dT) at four positions within the gap region of RNase H gapmer antisense oligonucleotides (ASOs) for reducing wild-type and mutant huntingtin mRNA in human patient fibroblasts. We show that these modifications can modulate processing of the ASO/RNA heteroduplexes by recombinant human RNase H1 in a position-dependent manner. We also created a structural model of the catalytic domain of human RNase H bound to ASO/RNA heteroduplexes to rationalize the activity and selectivity observations in cells and in the biochemical assays. Our results highlight the ability of chemical modifications in the gap region to produce profound changes in ASO behavior.

• 出版日期2015-10-1