5'-aminolevulinate synthase 1 mRNA (ALAS1 mRNA)

5'-aminolevulinate synthase 1 (ALAS1) is the rate-limiting enzyme in the heme biosynthetic pathway within the liver [1]. In individuals with acute hepatic porphyria (AHP), a deficiency in downstream enzymes leads to the compensatory upregulation of ALAS1, causing a toxic accumulation of heme precursors such as aminolevulinic acid (ALA) and porphobilinogen (PBG) [3, 4]. These neurotoxic intermediates are the primary drivers of acute porphyria attacks, which manifest as severe abdominal pain and neurological complications [4]. By targeting ALAS1 mRNA specifically in hepatocytes using RNA interference (RNAi) therapeutics like Givosiran, the translation of the ALAS1 enzyme is significantly reduced [2]. This intervention lowers the levels of circulating ALA and PBG, effectively preventing the neurovisceral crises associated with AHP [2, 3]. The use of N-acetylgalactosamine (GalNAc) conjugation allows for the specific delivery of these siRNA molecules to hepatocytes via the asialoglycoprotein receptor [2]. Sources: [1] UniProt (P13196); [2] FDA Givlaari (givosiran) Prescribing Information; [3] Balwani M, et al. NEJM (2020); [4] NIH Genetic and Rare Diseases Information Center (GARD).

Other names

ALAS-HALASH5-aminolevulinate synthase 1Aminolevulinate, delta-, synthase 1Delta-aminolevulinate synthase 1 mRNA

RNA interference (RNAi) mediated degradation of ALAS1 mRNA in hepatocytes to reduce the levels of the ALAS1 enzyme and neurotoxic heme intermediates.