The Mechanism of Small Interfering RNA (siRNA) Therapy. Synthetic double-stranded RNA containing an ALAS1-specific sequence is derivatized with N-acetylgalactosamine to target the asialoorosomucoid (galactose) receptor, which is expressed nearly exclusively on hepatocytes. Within the hepatocyte, the RNA is processed into approximately 20-bp fragments by a cellular enzyme (dicer), and then separated into single strands. The strand that is complementary to ALAS1 (the guide strand) binds to cellular ALAS1 messenger RNA (mRNA) and enters the RNA-induced silencing complex (RISC), where the new double-stranded RNA is cleaved by a group of factors that include argonaute, a ribonuclease. The result is a reduction in the level of delta ALA synthase 1 protein and decreased production of ALA. #Pathophys #Honc #Porphyria #siRNA #Therapy #NEJM
