PMID- 35121111
OWN - NLM
STAT- MEDLINE
DCOM- 20220411
LR  - 20240507
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 30
IP  - 4
DP  - 2022 Apr 6
TI  - Evaluation of cytosine base editing and adenine base editing as a potential 
      treatment for alpha-1 antitrypsin deficiency.
PG  - 1396-1406
LID - S1525-0016(22)00079-X [pii]
LID - 10.1016/j.ymthe.2022.01.040 [doi]
AB  - Alpha-1 antitrypsin deficiency (AATD) is a rare autosomal codominant disease 
      caused by mutations within the SERPINA1 gene. The most prevalent variant in 
      patients is PiZ SERPINA1, containing a single G > A transition mutation. PiZ 
      alpha-1 antitrypsin (AAT) is prone to misfolding, leading to the accumulation of 
      toxic aggregates within hepatocytes. In addition, the abnormally low level of AAT 
      secreted into circulation provides insufficient inhibition of neutrophil elastase 
      within the lungs, eventually causing emphysema. Cytosine and adenine base editors 
      enable the programmable conversion of C⋅G to T⋅A and A⋅T to G⋅C base pairs, 
      respectively. In this study, two different base editing approaches were 
      developed: use of a cytosine base editor to install a compensatory mutation 
      (p.Met374Ile) and use of an adenine base editor to mediate the correction of the 
      pathogenic PiZ mutation. After treatment with lipid nanoparticles formulated with 
      base editing reagents, PiZ-transgenic mice exhibited durable editing of SERPINA1 
      in the liver, increased serum AAT, and improved liver histology. These results 
      indicate that base editing has the potential to address both lung and liver 
      disease in AATD.
CI  - Copyright (c) 2022 The American Society of Gene and Cell Therapy. Published by 
      Elsevier Inc. All rights reserved.
FAU - Packer, Michael S
AU  - Packer MS
AD  - Beam Therapeutics, 238 Main Street, Cambridge, MA 02142, USA.
FAU - Chowdhary, Vivek
AU  - Chowdhary V
AD  - Gene Therapy Department, UMass Medical School, 55 Lake Avenue North, Worcester, 
      MA 01655, USA.
FAU - Lung, Genesis
AU  - Lung G
AD  - Beam Therapeutics, 238 Main Street, Cambridge, MA 02142, USA.
FAU - Cheng, Lo-I
AU  - Cheng LI
AD  - Beam Therapeutics, 238 Main Street, Cambridge, MA 02142, USA.
FAU - Aratyn-Schaus, Yvonne
AU  - Aratyn-Schaus Y
AD  - Beam Therapeutics, 238 Main Street, Cambridge, MA 02142, USA.
FAU - Leboeuf, Dominique
AU  - Leboeuf D
AD  - Beam Therapeutics, 238 Main Street, Cambridge, MA 02142, USA.
FAU - Smith, Sarah
AU  - Smith S
AD  - Beam Therapeutics, 238 Main Street, Cambridge, MA 02142, USA.
FAU - Shah, Aalok
AU  - Shah A
AD  - Beam Therapeutics, 238 Main Street, Cambridge, MA 02142, USA.
FAU - Chen, Delai
AU  - Chen D
AD  - Beam Therapeutics, 238 Main Street, Cambridge, MA 02142, USA.
FAU - Zieger, Marina
AU  - Zieger M
AD  - Gene Therapy Department, UMass Medical School, 55 Lake Avenue North, Worcester, 
      MA 01655, USA.
FAU - Cafferty, Brian J
AU  - Cafferty BJ
AD  - Beam Therapeutics, 238 Main Street, Cambridge, MA 02142, USA.
FAU - Yan, Bo
AU  - Yan B
AD  - Beam Therapeutics, 238 Main Street, Cambridge, MA 02142, USA.
FAU - Ciaramella, Giuseppe
AU  - Ciaramella G
AD  - Beam Therapeutics, 238 Main Street, Cambridge, MA 02142, USA.
FAU - Gregoire, Francine M
AU  - Gregoire FM
AD  - Beam Therapeutics, 238 Main Street, Cambridge, MA 02142, USA. Electronic address: 
      fgregoire@beamtx.com.
FAU - Mueller, Christian
AU  - Mueller C
AD  - Gene Therapy Department, UMass Medical School, 55 Lake Avenue North, Worcester, 
      MA 01655, USA. Electronic address: chris.mueller@umassmed.edu.
LA  - eng
GR  - P01 HL131471/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20220202
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (Lipid Nanoparticles)
RN  - 0 (Liposomes)
RN  - 0 (Serpina1a protein, mouse)
RN  - 0 (alpha 1-Antitrypsin)
RN  - 8J337D1HZY (Cytosine)
RN  - JAC85A2161 (Adenine)
SB  - IM
MH  - Adenine/chemistry/therapeutic use
MH  - Animals
MH  - Cytosine/chemistry/therapeutic use
MH  - *Gene Editing/methods
MH  - Humans
MH  - Liposomes
MH  - Mice
MH  - Mutation
MH  - Nanoparticles
MH  - alpha 1-Antitrypsin/genetics
MH  - *alpha 1-Antitrypsin Deficiency/genetics/pathology/therapy
PMC - PMC9077367
OTO - NOTNLM
OT  - alpha-1 antitrypsin
OT  - base editing
OT  - gene editing
OT  - lipid nanoparticles
OT  - mRNA
COIS- Declaration of interests M.S.P., G.L., L.C., Y.A.S., D.L., S.S., A.S., D.C., 
      B.J.C., B.Y., G.C., and F.M.G. are employees of and shareholders in Beam 
      Therapeutics. This work was funded in part by Beam Therapeutics, which develops 
      base editing therapeutics.
EDAT- 2022/02/06 06:00
MHDA- 2022/04/12 06:00
PMCR- 2023/04/06
CRDT- 2022/02/05 05:38
PHST- 2021/08/24 00:00 [received]
PHST- 2021/11/06 00:00 [revised]
PHST- 2022/01/28 00:00 [accepted]
PHST- 2022/02/06 06:00 [pubmed]
PHST- 2022/04/12 06:00 [medline]
PHST- 2022/02/05 05:38 [entrez]
PHST- 2023/04/06 00:00 [pmc-release]
AID - S1525-0016(22)00079-X [pii]
AID - 10.1016/j.ymthe.2022.01.040 [doi]
PST - ppublish
SO  - Mol Ther. 2022 Apr 6;30(4):1396-1406. doi: 10.1016/j.ymthe.2022.01.040. Epub 2022 
      Feb 2.