title: Using antisense technology to develop a novel therapy for α-1 antitrypsin deficient (AATD) liver disease and to model AATD lung disease.
abstract: Alpha-1 antitrypsin (AAT) is a serum protease inhibitor that belongs to the serpin superfamily. Mutations in AAT are associated with α-1 antitrypsin deficiency (AATD), a rare genetic disease with two distinct manifestations: AATD lung disease and AATD liver disease. AATD lung disease is caused by loss-of-function of AAT and can be treated with plasma-derived AAT. AATD liver disease is due to the aggregation and retention of mutant AAT protein in the liver; the only treatment available for AATD liver disease is liver transplantation. Here we demonstrate that antisense oligonucleotides (ASOs) targeting human AAT efficiently reduce levels of both short and long human AAT transcript in vitro and in transgenic mice, providing a novel therapy for AATD liver disease. In addition, ASO-mediated depletion of mouse AAT may offer a useful animal model for the investigation of AATD lung disease.
authors: Antisense Drug Discovery; Isis Pharmaceuticals; Carlsbad, CA USA.
authors: Shuling
authors: S
authors: Guo
authors: Antisense Drug Discovery; Isis Pharmaceuticals; Carlsbad, CA USA.
authors: Sheri L
authors: SL
authors: Booten
authors: Antisense Drug Discovery; Isis Pharmaceuticals; Carlsbad, CA USA.
authors: Andrew
authors: A
authors: Watt
authors: Antisense Drug Discovery; Isis Pharmaceuticals; Carlsbad, CA USA.
authors: Luis
authors: L
authors: Alvarado
authors: Antisense Drug Discovery; Isis Pharmaceuticals; Carlsbad, CA USA.
authors: Susan M
authors: SM
authors: Freier
authors: Department of Pediatrics; St. Louis University School of Medicine; St. Louis, MO USA.
authors: Jeffery H
authors: JH
authors: Teckman
authors: Antisense Drug Discovery; Isis Pharmaceuticals; Carlsbad, CA USA.
authors: Michael L
authors: ML
authors: McCaleb
authors: Antisense Drug Discovery; Isis Pharmaceuticals; Carlsbad, CA USA.
authors: Brett P
authors: BP
authors: Monia
keywords: AATD liver disease; AATD lung disease; PiZ; alpha-1 antitrypsin; alpha-1 antitrypsin deficiency; antisense oligonucleotide; antisense technology; serpin