TY - JOUR
T1 - RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice
AU - Yasuda, Makiko
AU - Gan, Lin
AU - Chen, Brenden
AU - Kadirvel, Senkottuvelan
AU - Yu, Chunli
AU - Phillips, John D.
AU - New, Maria I.
AU - Liebow, Abigail
AU - Fitzgerald, Kevin
AU - Querbes, William
AU - Desnick, Robert J.
PY - 2014/5/27
Y1 - 2014/5/27
N2 - 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 neuro-toxic porphyrin precursors 5-aminolevulinic acid (ALA) and por-phobilinogen (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 pre-clinical 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.
AB - 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 neuro-toxic porphyrin precursors 5-aminolevulinic acid (ALA) and por-phobilinogen (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 pre-clinical 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.
KW - Heme biosynthetic disorders
KW - Liver-targeted siRNA
KW - RNAi therapeutics
UR - http://www.scopus.com/inward/record.url?scp=84901660512&partnerID=8YFLogxK
U2 - 10.1073/pnas.1406228111
DO - 10.1073/pnas.1406228111
M3 - Article
C2 - 24821812
AN - SCOPUS:84901660512
SN - 0027-8424
VL - 111
SP - 7777
EP - 7782
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 21
ER -