PMID- 34217893
OWN - NLM
STAT- MEDLINE
DCOM- 20220331
LR  - 20221104
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 29
IP  - 11
DP  - 2021 Nov 3
TI  - Adenine base editing reduces misfolded protein accumulation and toxicity in 
      alpha-1 antitrypsin deficient patient iPSC-hepatocytes.
PG  - 3219-3229
LID - S1525-0016(21)00351-8 [pii]
LID - 10.1016/j.ymthe.2021.06.021 [doi]
AB  - Alpha-1 antitrypsin deficiency (AATD) is most commonly caused by the Z mutation, 
      a single-base substitution that leads to AAT protein misfolding and associated 
      liver and lung disease. In this study, we apply adenine base editors to correct 
      the Z mutation in patient induced pluripotent stem cells (iPSCs) and iPSC-derived 
      hepatocytes (iHeps). We demonstrate that correction of the Z mutation in patient 
      iPSCs reduces aberrant AAT accumulation and increases its secretion. Adenine base 
      editing (ABE) of differentiated iHeps decreases ER stress in edited cells, as 
      demonstrated by single-cell RNA sequencing. We find ABE to be highly efficient in 
      iPSCs and do not identify off-target genomic mutations by whole-genome 
      sequencing. These results reveal the feasibility and utility of base editing to 
      correct the Z mutation in AATD patient cells.
CI  - Copyright (c) 2021 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Werder, Rhiannon B
AU  - Werder RB
AD  - Center for Regenerative Medicine of Boston University and Boston Medical Center, 
      Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston 
      University School of Medicine, Boston, MA 02118, USA; QIMR Berghofer Medical 
      Research Institute, Herston, QLD 4006, Australia.
FAU - Kaserman, Joseph E
AU  - Kaserman JE
AD  - Center for Regenerative Medicine of Boston University and Boston Medical Center, 
      Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston 
      University School of Medicine, Boston, MA 02118, USA.
FAU - Packer, Michael S
AU  - Packer MS
AD  - Beam Therapeutics, Cambridge, MA 02139, USA.
FAU - Lindstrom-Vautrin, Jonathan
AU  - Lindstrom-Vautrin J
AD  - Center for Regenerative Medicine of Boston University and Boston Medical Center, 
      Boston, MA 02118, USA.
FAU - Villacorta-Martin, Carlos
AU  - Villacorta-Martin C
AD  - Center for Regenerative Medicine of Boston University and Boston Medical Center, 
      Boston, MA 02118, USA.
FAU - Young, Lauren E
AU  - Young LE
AD  - Beam Therapeutics, Cambridge, MA 02139, USA.
FAU - Aratyn-Schaus, Yvonne
AU  - Aratyn-Schaus Y
AD  - Beam Therapeutics, Cambridge, MA 02139, USA.
FAU - Gregoire, Francine
AU  - Gregoire F
AD  - Beam Therapeutics, Cambridge, MA 02139, USA.
FAU - Wilson, Andrew A
AU  - Wilson AA
AD  - Center for Regenerative Medicine of Boston University and Boston Medical Center, 
      Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston 
      University School of Medicine, Boston, MA 02118, USA. Electronic address: 
      awilson@bu.edu.
LA  - eng
GR  - R01 DK101501/DK/NIDDK NIH HHS/United States
GR  - R35 GM131726/GM/NIGMS NIH HHS/United States
GR  - S10 OD021587/OD/NIH HHS/United States
GR  - U01 TR001810/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210702
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (Biomarkers)
RN  - 0 (alpha 1-Antitrypsin)
RN  - JAC85A2161 (Adenine)
SB  - IM
MH  - *Adenine
MH  - Biomarkers
MH  - *CRISPR-Cas Systems
MH  - Cell Differentiation/genetics
MH  - Cells, Cultured
MH  - Endoplasmic Reticulum Stress
MH  - *Gene Editing
MH  - Gene Expression
MH  - Hepatocytes/cytology/*metabolism
MH  - Humans
MH  - Induced Pluripotent Stem Cells/cytology/*metabolism
MH  - Mutation
MH  - alpha 1-Antitrypsin/chemistry/*genetics
MH  - alpha 1-Antitrypsin Deficiency/*genetics/*therapy
PMC - PMC8571173
OTO - NOTNLM
OT  - adenine base editor
OT  - alpha-1 antitrypsin deficiency
OT  - base edit
OT  - hepatocyte
OT  - human induced pluripotent stem cells
OT  - iHep
OT  - iPSC
OT  - single cell RNA sequencing
OT  - whole genome sequencing
COIS- Declaration of interests Support for this work was provided in the form of a 
      research grant from Beam Therapeutics to A.A.W. M.S.P., L.E.Y., Y.A.-S., and F.G. 
      are employed by Beam Therapeutics and contributed to data collection, data 
      analysis, and manuscript preparation.
EDAT- 2021/07/05 06:00
MHDA- 2022/04/01 06:00
PMCR- 2022/11/03
CRDT- 2021/07/04 20:42
PHST- 2021/04/23 00:00 [received]
PHST- 2021/06/10 00:00 [revised]
PHST- 2021/06/25 00:00 [accepted]
PHST- 2021/07/05 06:00 [pubmed]
PHST- 2022/04/01 06:00 [medline]
PHST- 2021/07/04 20:42 [entrez]
PHST- 2022/11/03 00:00 [pmc-release]
AID - S1525-0016(21)00351-8 [pii]
AID - 10.1016/j.ymthe.2021.06.021 [doi]
PST - ppublish
SO  - Mol Ther. 2021 Nov 3;29(11):3219-3229. doi: 10.1016/j.ymthe.2021.06.021. Epub 
      2021 Jul 2.