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

Significance There is an unmet need for a more effective, faster-acting, and safer therapy for the life-threatening acute neurovisceral attacks that occur in the acute hepatic porphyrias. Recent studies indicate that the acute attacks are primarily caused by the neurotoxic porphyrin precursors 5-aminolevulinic acid and porphobilinogen, which accumulate as a consequence of the markedly induced expression of hepatic 5-aminolevulinic acid synthase 1 (ALAS1). Here, we demonstrate that liver-targeted small interfering RNAs specific for Alas1 are highly effective in preventing and treating the biochemically induced acute attacks in a mouse model of acute intermittent porphyria, the most common acute hepatic porphyria. These preclinical studies provide proof-of-concept for the clinical development of RNAi-mediated therapy for the acute porphyric attacks. 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.