Circular RNA interference effector molecules (WO10084371)

Just over a decade after the discovery of RNA interference (RNAi), the RNAi field has begun travelling the bumpy road towards the clinic. Notwithstanding this extraordinarily rapid progress, and despite holding great promise for substantial future clinical impact, RNAi-inducing agents unfortunately exhibit certain physico-chemical and pharmacokinetic drawbacks. The patent application WO10084371 utilizes the exquisite biological mechanism of auto-catalytic intron splicing to generate circularized interfering RNAs (ciRNAs) in order to remedy the issue of rapid nuclease-mediated degradation of RNAi-inducers. The present patent evaluation assesses the utility of the ciRNAs in light of commonly used nucleotide modification strategies for modulating the properties of siRNAs, as well as scrutinizes the experimental data substantiating the patent application in question. The ciRNAs disclosed in WO10084371 exhibit potency on par with exogenously introduced short hairpin RNAs, albeit displaying increased exonuclease resistance. However, experimental validation as to the exact silencing mechanism is sparse, although the potential Dicer-substrate function of the ciRNAs is indeed a promising aspect. Despite the novel, elegant approach of WO10084371, the current gold standard nucleotide modifications appear to deliver sufficient stability for therapeutic applications, meaning that solving the issue of siRNA delivery still remains the major hurdle for clinical success.