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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Vydáno v:	Proceedings of the National Academy of Sciences - PNAS Ročník 111; číslo 21; s. 7777
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 27.05.2014
Témata:	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
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Undefined-3
ISSN:	1091-6490 1091-6490
DOI:	10.1073/pnas.1406228111