Off-target mRNAs with partial complementarity to the LRG1-targeting guide strand (LRG1 off-target mRNAs)

Off-target mRNAs with partial complementarity to the LRG1-targeting guide strand represent a class of unintended molecular interactions occurring during the use of RNA interference (RNAi) or CRISPR-based therapies directed at Leucine-rich alpha-2-glycoprotein 1 (LRG1). LRG1 is a glycoprotein known to promote pathological angiogenesis by modulating TGF-beta signaling, making it a therapeutic target for conditions like neovascular age-related macular degeneration and certain cancers (Wang et al., 2013, Nature). When a guide strand, such as an siRNA or gRNA, is designed to target LRG1, it may inadvertently bind to other mRNA transcripts that possess similar sequences. This binding can lead to the degradation or translational repression of these non-target transcripts (Jackson et al., 2003, Nature Biotechnology). This off-target activity is a significant concern in drug development as it can result in the loss of function of unrelated genes, potentially leading to cellular toxicity or adverse clinical outcomes (O'Connor et al., 2021, JCI). Strategies to mitigate these effects include optimized sequence design, chemical modifications of the oligonucleotides, and rigorous bioinformatic screening to ensure high specificity for the LRG1 transcript.

Other names

Off-target transcriptsNon-specific mRNA targetsLRG1 siRNA off-targetsLRG1 CRISPR off-targetsSeed-sequence mediated off-targets

Unintended binding and degradation or translational inhibition of non-target mRNAs due to sequence homology with the LRG1-targeting guide strand.