Off-target messenger RNAs of Rhodopsin-targeting RNA interference (RHO-RNAi Off-targets)

This target category refers to the collection of endogenous messenger RNAs (mRNAs) that are unintentionally suppressed by RNA interference (RNAi) molecules designed to target the Rhodopsin (RHO) gene. In therapeutic contexts, such as the treatment of Autosomal Dominant Retinitis Pigmentosa (adRP), shRNAs or miRNAs are used to knockdown mutant RHO expression; however, these molecules can also bind to other transcripts with partial sequence complementarity (Jackson et al., 2003). This binding typically occurs between the 'seed region' of the small RNA and the 3' untranslated region (UTR) of the off-target mRNA, leading to its degradation or translational inhibition (Lewis et al., 2005). Such off-target effects are a significant concern in gene therapy development, as they can result in the silencing of genes essential for retinal health or general cellular homeostasis (Millington-Ward et al., 2011). Strategies to mitigate these effects include the use of 'microRNA-mimetic' scaffolds and rigorous bioinformatic filtering to ensure that the chosen sequences have minimal complementarity to the broader transcriptome (Birmingham et al., 2006). Understanding and monitoring these off-target mRNAs is vital for ensuring the safety and long-term tolerability of RHO-targeting genetic medicines.

Other names

RHO RNAi off-targetsSeed-matched off-target transcriptsUnintended mRNA targetsPartial complementarity off-targets

Unintended post-transcriptional gene silencing via the RNA-induced silencing complex (RISC) through partial complementarity to the 3' untranslated regions (UTRs) of non-target transcripts.