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

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-aminolev...

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Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 21; p. 7777
Main Authors: Yasuda, Makiko, Gan, Lin, Chen, Brenden, Kadirvel, Senkottuvelan, Yu, Chunli, Phillips, John D, New, Maria I, Liebow, Abigail, Fitzgerald, Kevin, Querbes, William, Desnick, Robert J
Format: Journal Article
Language:English
Published: United States 27.05.2014
Subjects:
5-Aminolevulinate Synthetase - genetics
5-Aminolevulinate Synthetase - metabolism
Analysis of Variance
Animals
Blotting, Western
Drug Evaluation, Preclinical
Electrophoresis, Polyacrylamide Gel
Female
Liver - metabolism
Mice
Mice, Inbred C57BL
Particle Size
Porphyria, Acute Intermittent - prevention & control
Real-Time Polymerase Chain Reaction
RNA Interference - drug effects
RNA Interference - immunology
RNA, Small Interfering - pharmacology
RNAi therapeutics
heme biosynthetic disorders
liver-targeted siRNA
ISSN:1091-6490, 1091-6490
Online Access:Get more information
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Summary: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.
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ISSN:1091-6490
1091-6490
DOI:10.1073/pnas.1406228111