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Antisense oligonucleotide treatment ameliorates alpha-1 antitrypsin–related liver disease in mice
Shuling Guo, … , Michael L. McCaleb, Brett P. Monia
Shuling Guo, … , Michael L. McCaleb, Brett P. Monia
Published December 20, 2013
Citation Information: J Clin Invest. 2014;124(1):251-261. https://doi.org/10.1172/JCI67968.
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Research Article Article has an altmetric score of 23

Antisense oligonucleotide treatment ameliorates alpha-1 antitrypsin–related liver disease in mice

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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

Shuling Guo, Sheri L. Booten, Mariam Aghajan, Gene Hung, Chenguang Zhao, Keith Blomenkamp, Danielle Gattis, Andrew Watt, Susan M. Freier, Jeffery H. Teckman, Michael L. McCaleb, Brett P. Monia

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Figure 3

AAT-ASO treatment reversed liver globule accumulation and reduced hAAT in all hepatocytes in PiZ mice.

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AAT-ASO treatment reversed liver globule accumulation and reduced hAAT i...
(A) Sixteen-week-old PiZ mice were treated for 20 weeks with 50 mg/kg/wk AAT-ASO via subcutaneous injection. Soluble and insoluble fractions from PiZ livers were analyzed by Western blot analysis with an anti-hAAT antibody. GAPDH was used as a loading control. (B) Quantitation of liver soluble AAT Western blot data shown in A. (C) Quantitation of liver insoluble AAT Western blot data shown in A. (D) ASO uptake by hepatocytes in PiZ mice. ASO was visualized by an antibody reactive to the ASO backbone. Arrows indicates perinuclear vesicle staining in hepatocytes; arrowheads indicates nonparenchymal cells. Scale bar: 50 μm; 20 μm (inset). (E) hAAT transcript visualized by in situ hybridization (QuantiGene ViewRNA, Affymetrix). The arrow indicates a globule-containing area; the arrowhead indicates a globule-devoid area. Scale bar: 100 μm; 20 μm (inset). Results represent mean ± range (n = 2 for baseline, n = 4 for treatment groups).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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