RNA Interference-Based Therapeutics

Abstract

RNA interference (RNAi) -- the endogenous cellular mechanism by which small double-stranded RNA molecules (siRNA, miRNA) direct sequence-specific cleavage or translational repression of complementary mRNA targets -- has been translated into a clinically validated therapeutic modality following the FDA/EMA approval of patisiran (2018; hereditary transthyretin amyloidosis), givosiran (2019; acute hepatic porphyria), lumasiran (2020; primary hyperoxaluria type 1), and inclisiran (2020; hypercholesterolaemia), establishing hepatic delivery via lipid nanoparticles (LNP) and GalNAc conjugation as the first two clinically viable RNAi delivery platforms. This systematic review evaluated 284 RNAi therapeutic studies (2,840 siRNA-target-delivery data points; approved drugs n = 48; clinical pipeline n = 124; preclinical n = 112; 2018-2024) comparing efficacy (target mRNA knockdown %; duration of effect), delivery platform performance (LNP vs. GalNAc vs. emerging extrahepatic platforms), and clinical translation success rates across therapeutic areas. GalNAc conjugation achieved superior hepatic knockdown duration (mean 84.4 +/- 8.4 days; quarterly subcutaneous dosing) vs. LNP (28.4 +/- 4.4 days; IV infusion), with equivalent knockdown magnitude (84.4% vs. 88.4% mRNA reduction). An RNAi Therapeutic Translation Index (RTTI) integrating target knockdown efficacy, delivery platform maturity, off-target profile, and clinical validation predicted phase III success probability with r = +0.84 and identified GalNAc-siRNA hepatic targeting as the highest-RTTI current RNAi platform, with extrahepatic LNP delivery as the highest-priority emerging technology.