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: 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 21 Pg. 7777-82 (May 27 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 24821812 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Validation Study)

Chemical References

• RNA, Small Interfering
• 5-Aminolevulinate Synthetase

Topics

• 5-Aminolevulinate Synthetase (genetics, 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)
• RNA Interference (drug effects, immunology)
• RNA, Small Interfering (pharmacology)
• Real-Time Polymerase Chain Reaction