PMID- 29641323
OWN - NLM
STAT- MEDLINE
DCOM- 20190520
LR  - 20190520
IS  - 1557-7422 (Electronic)
IS  - 1043-0342 (Linking)
VI  - 29
IP  - 8
DP  - 2018 Aug
TI  - Amelioration of Alpha-1 Antitrypsin Deficiency Diseases with Genome Editing in 
      Transgenic Mice.
PG  - 861-873
LID - 10.1089/hum.2017.227 [doi]
AB  - Alpha-1 antitrypsin deficiency (AATD) is a hereditary liver disease caused by 
      mutations in the SERPINA1 serine protease inhibitor gene. Most severe patients 
      are homozygous for PiZ alleles (PiZZ; amino acid E324K), which lead to protein 
      aggregates in hepatocytes and reduced circulating levels of AAT. The liver 
      aggregates typically lead to fibrosis, cirrhosis, and hepatocellular carcinoma, 
      and the reduced circulating AAT levels can lead to emphysema and chronic 
      obstructive pulmonary diseases. In this study, two CRISPR/Cas9 gene editing 
      approaches were used to decrease liver aggregates and increase systemic AAT-M 
      levels in the PiZ transgenic mouse. In the first approach, AAT expression in 
      hepatocytes was reduced more than 98% following the systemic delivery of 
      AAV8-CRISPR targeting exon 2 of hSERPINA1, leading to reduced aggregates in 
      hepatocytes. In the second approach, a second adeno-associated virus, which 
      provided the donor template to correct the Z mutation, was also administered. 
      These treated mice had reduced AAT expression (> 98%) and a low level (5%) of 
      wildtype AAT-M mRNA. Taken together, this study shows that CRISPR gene editing 
      can efficiently reduce liver expression of AAT-Z and restore modest levels of 
      wildtype AAT-M in a mouse model of AATD, raising the possibility of CRISPR gene 
      editing therapeutic for AATD.
FAU - Shen, Shen
AU  - Shen S
AD  - 1 Editas Medicine, Cambridge, Massachusetts, St. Louis University School of 
      Medicine , St. Louis, Missouri.
FAU - Sanchez, Minerva E
AU  - Sanchez ME
AD  - 1 Editas Medicine, Cambridge, Massachusetts, St. Louis University School of 
      Medicine , St. Louis, Missouri.
FAU - Blomenkamp, Keith
AU  - Blomenkamp K
AD  - 2 Department of Pediatrics, St. Louis University School of Medicine , St. Louis, 
      Missouri.
FAU - Corcoran, Erik M
AU  - Corcoran EM
AD  - 1 Editas Medicine, Cambridge, Massachusetts, St. Louis University School of 
      Medicine , St. Louis, Missouri.
FAU - Marco, Eugenio
AU  - Marco E
AD  - 1 Editas Medicine, Cambridge, Massachusetts, St. Louis University School of 
      Medicine , St. Louis, Missouri.
FAU - Yudkoff, Clifford J
AU  - Yudkoff CJ
AD  - 1 Editas Medicine, Cambridge, Massachusetts, St. Louis University School of 
      Medicine , St. Louis, Missouri.
FAU - Jiang, Haiyan
AU  - Jiang H
AD  - 1 Editas Medicine, Cambridge, Massachusetts, St. Louis University School of 
      Medicine , St. Louis, Missouri.
FAU - Teckman, Jeffrey H
AU  - Teckman JH
AD  - 2 Department of Pediatrics, St. Louis University School of Medicine , St. Louis, 
      Missouri.
FAU - Bumcrot, David
AU  - Bumcrot D
AD  - 1 Editas Medicine, Cambridge, Massachusetts, St. Louis University School of 
      Medicine , St. Louis, Missouri.
FAU - Albright, Charles F
AU  - Albright CF
AD  - 1 Editas Medicine, Cambridge, Massachusetts, St. Louis University School of 
      Medicine , St. Louis, Missouri.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180622
PL  - United States
TA  - Hum Gene Ther
JT  - Human gene therapy
JID - 9008950
RN  - 0 (Serpina1a protein, mouse)
RN  - 0 (alpha 1-Antitrypsin)
SB  - IM
MH  - Alleles
MH  - Animals
MH  - CRISPR-Cas Systems/*genetics
MH  - Dependovirus/genetics
MH  - Disease Models, Animal
MH  - Gene Editing
MH  - *Genetic Therapy
MH  - Genetic Vectors/therapeutic use
MH  - Hepatocytes/pathology
MH  - Homozygote
MH  - Humans
MH  - Liver/metabolism/pathology
MH  - Mice
MH  - Mice, Transgenic/genetics
MH  - Mutation
MH  - alpha 1-Antitrypsin/*genetics
MH  - alpha 1-Antitrypsin Deficiency/genetics/pathology/*therapy
OTO - NOTNLM
OT  - AAV
OT  - CRISPR/Cas9
OT  - alpha-1 antitrypsin deficiency
OT  - gene correction
OT  - gene therapy
EDAT- 2018/04/12 06:00
MHDA- 2019/05/21 06:00
CRDT- 2018/04/12 06:00
PHST- 2018/04/12 06:00 [pubmed]
PHST- 2019/05/21 06:00 [medline]
PHST- 2018/04/12 06:00 [entrez]
AID - 10.1089/hum.2017.227 [doi]
PST - ppublish
SO  - Hum Gene Ther. 2018 Aug;29(8):861-873. doi: 10.1089/hum.2017.227. Epub 2018 Jun 
      22.