title: RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice.
abstract: The acute hepatic porphyrias are inherited disorders of heme biosynthesis characterized by life-threatening acute neurovisceral attacks. Factors that induce the expression of hepatic 5-aminolevulinic acid synthase 1 (ALAS1) result in the accumulation of the neurotoxic porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), which recent studies indicate are primarily responsible for the acute attacks. Current treatment of these attacks involves i.v. administration of hemin, but a faster-acting, more effective, and safer therapy is needed. Here, we describe preclinical studies of liver-directed small interfering RNAs (siRNAs) targeting Alas1 (Alas1-siRNAs) in a mouse model of acute intermittent porphyria, the most common acute hepatic porphyria. A single i.v. dose of Alas1-siRNA prevented the phenobarbital-induced biochemical acute attacks for approximately 2 wk. Injection of Alas1-siRNA during an induced acute attack significantly decreased plasma ALA and PBG levels within 8 h, more rapidly and effectively than a single hemin infusion. Alas1-siRNA was well tolerated and a therapeutic dose did not cause hepatic heme deficiency. These studies provide proof-of-concept for the clinical development of RNA interference therapy for the prevention and treatment of the acute attacks of the acute hepatic porphyrias.
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Makiko
authors.initials: M
authors.lastname: Yasuda
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Lin
authors.initials: L
authors.lastname: Gan
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Brenden
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Senkottuvelan
authors.initials: S
authors.lastname: Kadirvel
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Chunli
authors.initials: C
authors.lastname: Yu
authors.affiliation: Hematology Division, University of Utah School of Medicine, Salt Lake City, UT 84132;
authors.forename: John D
authors.initials: JD
authors.lastname: Phillips
authors.affiliation: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029; and maria.new@mssm.edu robert.desnick@mssm.edu.
authors.forename: Maria I
authors.initials: MI
authors.lastname: New
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, MA 02142.
authors.forename: Abigail
authors.initials: A
authors.lastname: Liebow
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, MA 02142.
authors.forename: Kevin
authors.initials: K
authors.lastname: Fitzgerald
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, MA 02142.
authors.forename: William
authors.initials: W
authors.lastname: Querbes
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029; maria.new@mssm.edu robert.desnick@mssm.edu.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
mesh_terms: D000624:5-Aminolevulinate Synthetase / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D004353:Drug Evaluation, Preclinical; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010316:Particle Size; D017118:Porphyria, Acute Intermittent / Q000517:prevention & control*; D034622:RNA Interference / Q000187:drug effects / Q000276:immunology*; D034741:RNA, Small Interfering / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D034741:RNA, Small Interfering; D000624:5-Aminolevulinate Synthetase
keywords: RNAi therapeutics; heme biosynthetic disorders; liver-targeted siRNA