Open AccessLikelihood of Nonspecific Activity of Gapmer Antisense Oligonucleotides Is Associated with Relative Hybridization Free Energy
Author(s) -
Andrew T. Watt,
Grant Swayze,
Eric E. Swayze,
Susan M. Freier
Publication year - 2020
Publication title -
nucleic acid therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.255
H-Index - 67
eISSN - 2159-3345
pISSN - 2159-3337
DOI - 10.1089/nat.2020.0847
Subject(s) - oligonucleotide , chemistry , biophysics , microbiology and biotechnology , biology , biochemistry , gene
Reduction of matched and nearly complementary unintended transcripts was evaluated for 96 antisense oligonucleotides (ASOs) and 832 nearly matched unintended transcripts. The ASOs were 16-20 nucleotide "gapmers" with a gap of 8-10 DNA residues and 2'-O-methoxy-ethyl or constrained-ethyl substitutions in the wings. Most unintended transcripts were not reduced or were reduced with a potency more than 10-fold weaker than the intended transcript. For the unintended transcripts that were reduced, a strong correlation between relative potency of the intended versus the unintended transcript with predicted free energy of hybridization was observed. These results suggest ASO selectivity should be evaluated by testing for reduction of the unintended transcripts predicted to bind most stably to the ASO.