RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice

Makiko Yasuda, Lin Gan, Brenden Chen, Senkottuvelan Kadirvel, Chunli Yu, John D. Phillips, Maria I. New, Abigail Liebow, Kevin Fitzgerald, William Querbes, Robert J. Desnick

Research output: Contribution to journalArticlepeer-review

94 Scopus citations

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 neuro-toxic porphyrin precursors 5-aminolevulinic acid (ALA) and por-phobilinogen (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 pre-clinical 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.

Original languageEnglish
Pages (from-to)7777-7782
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number21
DOIs
StatePublished - 27 May 2014

Keywords

  • Heme biosynthetic disorders
  • Liver-targeted siRNA
  • RNAi therapeutics

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