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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Veröffentlicht in:	Proceedings of the National Academy of Sciences - PNAS Jg. 111; H. 21; S. 7777
Hauptverfasser:	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
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States 27.05.2014
Schlagworte:	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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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.
AbstractList	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.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. 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.
Author	Yu, Chunli Liebow, Abigail Desnick, Robert J Gan, Lin Yasuda, Makiko Phillips, John D Querbes, William Chen, Brenden Kadirvel, Senkottuvelan New, Maria I Fitzgerald, Kevin
Author_xml	– sequence: 1 givenname: Makiko surname: Yasuda fullname: Yasuda, Makiko organization: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029 – sequence: 2 givenname: Lin surname: Gan fullname: Gan, Lin organization: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029 – sequence: 3 givenname: Brenden surname: Chen fullname: Chen, Brenden organization: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029 – sequence: 4 givenname: Senkottuvelan surname: Kadirvel fullname: Kadirvel, Senkottuvelan organization: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029 – sequence: 5 givenname: Chunli surname: Yu fullname: Yu, Chunli organization: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029 – sequence: 6 givenname: John D surname: Phillips fullname: Phillips, John D organization: Hematology Division, University of Utah School of Medicine, Salt Lake City, UT 84132 – sequence: 7 givenname: Maria I surname: New fullname: New, Maria I email: maria.new@mssm.edu, robert.desnick@mssm.edu organization: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029; and maria.new@mssm.edu robert.desnick@mssm.edu – sequence: 8 givenname: Abigail surname: Liebow fullname: Liebow, Abigail organization: Alnylam Pharmaceuticals, Cambridge, MA 02142 – sequence: 9 givenname: Kevin surname: Fitzgerald fullname: Fitzgerald, Kevin organization: Alnylam Pharmaceuticals, Cambridge, MA 02142 – sequence: 10 givenname: William surname: Querbes fullname: Querbes, William organization: Alnylam Pharmaceuticals, Cambridge, MA 02142 – sequence: 11 givenname: Robert J surname: Desnick fullname: Desnick, Robert J email: maria.new@mssm.edu, robert.desnick@mssm.edu organization: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029; maria.new@mssm.edu robert.desnick@mssm.edu
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Snippet	The acute hepatic porphyrias are inherited disorders of heme biosynthesis characterized by life-threatening acute neurovisceral attacks. Factors that induce...
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SubjectTerms	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
Title	RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice
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