PMID- 24355919
OWN - NLM
STAT- MEDLINE
DCOM- 20140303
LR  - 20220311
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 124
IP  - 1
DP  - 2014 Jan
TI  - Antisense oligonucleotide treatment ameliorates alpha-1 antitrypsin-related liver 
      disease in mice.
PG  - 251-61
LID - 67968 [pii]
LID - 10.1172/JCI67968 [doi]
AB  - 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.
FAU - Guo, Shuling
AU  - Guo S
FAU - Booten, Sheri L
AU  - Booten SL
FAU - Aghajan, Mariam
AU  - Aghajan M
FAU - Hung, Gene
AU  - Hung G
FAU - Zhao, Chenguang
AU  - Zhao C
FAU - Blomenkamp, Keith
AU  - Blomenkamp K
FAU - Gattis, Danielle
AU  - Gattis D
FAU - Watt, Andrew
AU  - Watt A
FAU - Freier, Susan M
AU  - Freier SM
FAU - Teckman, Jeffery H
AU  - Teckman JH
FAU - McCaleb, Michael L
AU  - McCaleb ML
FAU - Monia, Brett P
AU  - Monia BP
LA  - eng
PT  - Journal Article
DEP - 20131220
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Oligonucleotides, Antisense)
RN  - 0 (RNA, Messenger)
RN  - 0 (alpha 1-Antitrypsin)
SB  - IM
MH  - Animals
MH  - Female
MH  - Gene Knockdown Techniques
MH  - Hep G2 Cells
MH  - Hepatocytes/enzymology
MH  - Humans
MH  - Liver/enzymology/pathology
MH  - Liver Cirrhosis/enzymology/genetics/therapy
MH  - Macaca fascicularis
MH  - Male
MH  - Mice
MH  - Mice, Transgenic
MH  - Oligonucleotides, Antisense/*genetics
MH  - RNA, Messenger/genetics/metabolism
MH  - alpha 1-Antitrypsin/genetics/metabolism
MH  - alpha 1-Antitrypsin Deficiency/enzymology/genetics/*therapy
PMC - PMC3871221
EDAT- 2013/12/21 06:00
MHDA- 2014/03/04 06:00
PMCR- 2013/12/20
CRDT- 2013/12/21 06:00
PHST- 2012/11/27 00:00 [received]
PHST- 2013/10/15 00:00 [accepted]
PHST- 2013/12/21 06:00 [entrez]
PHST- 2013/12/21 06:00 [pubmed]
PHST- 2014/03/04 06:00 [medline]
PHST- 2013/12/20 00:00 [pmc-release]
AID - 67968 [pii]
AID - 10.1172/JCI67968 [doi]
PST - ppublish
SO  - J Clin Invest. 2014 Jan;124(1):251-61. doi: 10.1172/JCI67968. Epub 2013 Dec 20.