Off-target mRNAs with partial complementarity to the MYC antisense sequence

Off-target mRNAs with partial complementarity to the MYC antisense sequence represent a class of unintended molecular targets encountered during the development of antisense oligonucleotide (ASO) or siRNA therapies directed against the MYC oncogene. MYC is a potent transcription factor that regulates approximately 15% of all human genes, making it a high-priority target in oncology (Dang, 2012, PubMed: 22464321). However, antisense sequences designed to bind MYC mRNA can also hybridize with other transcripts that share partial sequence homology, particularly in the seed region or through short complementary stretches (Swayze et al., 2007, PubMed: 17307863). This interaction often leads to the degradation of these off-target mRNAs by RNase H or the inhibition of their translation, resulting in unintended biological consequences and potential toxicity (Lindow et al., 2012, PubMed: 22538119). Such off-target effects are a major hurdle in the clinical translation of MYC inhibitors like AVI-4126, as they can confound efficacy data and cause adverse events (Iversen et al., 2003, PubMed: 12663924). Minimizing these interactions requires sophisticated bioinformatics screening and chemical modifications to the oligonucleotide backbone to enhance binding specificity (Egli and Manoharan, 2023, PubMed: 37130878).

Other names

Unintended mRNA targetsOff-target transcriptsSeed-match off-targetsNon-specific antisense targetsHybridization-dependent off-targets

Hybridization-dependent knockdown of non-target transcripts via RNase H-mediated cleavage or steric hindrance of translation.