RNAi-mediated silencing of hepaticAlas1effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice

• DOI: 10.1073/pnas.1406228111
• Publication Date: 2014-05-13T08:53:58Z
• Authors: Makiko Yasuda; Lin Gan; Brenden Chen; Senkottuvelan Kad...; Chunli Yu; John D. Phillips; Maria I. New; Abigail Liebow; Kevin Fitzgerald; William Querbes; Robert J. Desnick
• Keywords: Analysis of Variance; 0303 health sciences; Blotting, Western; Drug Evaluation, Preclinical; Real-Time Polymerase Chain Reaction; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Liver; Porphyria, Acute Intermittent; Animals; Electrophoresis, Polyacrylamide Gel; Female; RNA Interference; Particle Size; RNA, Small Interfering; 5-Aminolevulinate Synthetase

The acute hepatic porphyrias are inherited disorders of heme biosynthesis characterized by life-threatening neurovisceral attacks. Factors that induce the expression 5-aminolevulinic acid synthase 1 (ALAS1) result in accumulation neurotoxic porphyrin precursors (ALA) and porphobilinogen (PBG), which recent studies indicate primarily responsible for Current treatment these attacks involves i.v. administration hemin, but a faster-acting, more effective, safer therapy is needed. Here, we describe preclinical liver-directed small interfering RNAs (siRNAs) targeting Alas1 (Alas1-siRNAs) mouse model intermittent porphyria, most common porphyria. A single dose Alas1-siRNA prevented phenobarbital-induced biochemical approximately 2 wk. Injection during an induced attack significantly decreased plasma ALA PBG levels within 8 h, rapidly effectively than hemin infusion. was well tolerated therapeutic did not cause deficiency. These provide proof-of-concept clinical development RNA interference prevention porphyrias.