title: Antisense oligonucleotide treatment ameliorates alpha-1 antitrypsin-related liver disease in mice.
abstract: Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disease that results from mutations in the alpha-1 antitrypsin (AAT) gene. The mutant AAT protein aggregates and accumulates in the liver leading to AATD liver disease, which is only treatable by liver transplant. The PiZ transgenic mouse strain expresses a human AAT (hAAT) transgene that contains the AATD-associated Glu342Lys mutation. PiZ mice exhibit many AATD symptoms, including AAT protein aggregates, increased hepatocyte death, and liver fibrosis. In the present study, we systemically treated PiZ mice with an antisense oligonucleotide targeted against hAAT (AAT-ASO) and found reductions in circulating levels of AAT and both soluble and aggregated AAT protein in the liver. Furthermore, AAT-ASO administration in these animals stopped liver disease progression after short-term treatment, reversed liver disease after long-term treatment, and prevented liver disease in young animals. Additionally, antisense oligonucleotide treatment markedly decreased liver fibrosis in this mouse model. Administration of AAT-ASO in nonhuman primates led to an approximately 80% reduction in levels of circulating normal AAT, demonstrating potential for this approach in higher species. Antisense oligonucleotides thus represent a promising therapy for AATD liver disease.
authors.forename: Shuling
authors.initials: S
authors.lastname: Guo
authors.forename: Sheri L
authors.initials: SL
authors.lastname: Booten
authors.forename: Mariam
authors.initials: M
authors.lastname: Aghajan
authors.forename: Gene
authors.initials: G
authors.lastname: Hung
authors.forename: Chenguang
authors.initials: C
authors.lastname: Zhao
authors.forename: Keith
authors.initials: K
authors.lastname: Blomenkamp
authors.forename: Danielle
authors.initials: D
authors.lastname: Gattis
authors.forename: Andrew
authors.initials: A
authors.lastname: Watt
authors.forename: Susan M
authors.initials: SM
authors.lastname: Freier
authors.forename: Jeffery H
authors.initials: JH
authors.lastname: Teckman
authors.forename: Michael L
authors.initials: ML
authors.lastname: McCaleb
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
mesh_terms: D000818:Animals; D005260:Female; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000201:enzymology; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008103:Liver Cirrhosis / Q000201:enzymology / Q000235:genetics / Q000628:therapy; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016376:Oligonucleotides, Antisense / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000378:metabolism; D019896:alpha 1-Antitrypsin Deficiency / Q000201:enzymology / Q000235:genetics / Q000628:therapy*
chemical_list: D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D000515:alpha 1-Antitrypsin