PMID- 35811581
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230707
IS  - 2768-1556 (Electronic)
IS  - 2768-1556 (Print)
IS  - 2768-1556 (Linking)
VI  - 1
IP  - 3
DP  - 2022 Jun 1
TI  - Adenine Base Editing In Vivo with a Single Adeno-Associated Virus Vector.
PG  - 285-299
LID - 10.1089/genbio.2022.0015 [doi]
AB  - Base editors (BEs) have opened new avenues for the treatment of genetic diseases. 
      However, advances in delivery approaches are needed to enable disease targeting 
      of a broad range of tissues and cell types. Adeno-associated virus (AAV) vectors 
      remain one of the most promising delivery vehicles for gene therapies. Currently, 
      most BE/guide combinations and their promoters exceed the packaging limit ( approximately 5 kb) 
      of AAVs. Dual-AAV delivery strategies often require high viral doses that impose 
      safety concerns. In this study, we engineered an adenine base editor (ABE) using 
      a compact Cas9 from Neisseria meningitidis (Nme2Cas9). Compared with the 
      well-characterized Streptococcus pyogenes Cas9-containing ABEs, ABEs using 
      Nme2Cas9 (Nme2-ABE) possess a distinct protospacer adjacent motif (N(4)CC) and 
      editing window, exhibit fewer off-target effects, and can efficiently install 
      therapeutically relevant mutations in both human and mouse genomes. Importantly, 
      we show that in vivo delivery of Nme2-ABE and its guide RNA by a single AAV 
      vector can efficiently edit mouse genomic loci and revert the disease mutation 
      and phenotype in an adult mouse model of tyrosinemia. We anticipate that 
      Nme2-ABE, by virtue of its compact size and broad targeting range, will enable a 
      range of therapeutic applications with improved safety and efficacy due in part 
      to packaging in a single-vector system.
CI  - Copyright 2022, Mary Ann Liebert, Inc., publishers.
FAU - Zhang, Han
AU  - Zhang H
AD  - RNA Therapeutics Institute, University of Massachusetts Chan Medical School, 
      Worcester, Massachusetts, USA.
FAU - Bamidele, Nathan
AU  - Bamidele N
AUID- ORCID: 0000-0001-9051-5531
AD  - RNA Therapeutics Institute, University of Massachusetts Chan Medical School, 
      Worcester, Massachusetts, USA.
FAU - Liu, Pengpeng
AU  - Liu P
AD  - Departments of Molecular, Cell and Cancer Biology, University of Massachusetts 
      Chan Medical School, Worcester, Massachusetts, USA.
FAU - Ojelabi, Ogooluwa
AU  - Ojelabi O
AUID- ORCID: 0000-0003-3931-5555
AD  - RNA Therapeutics Institute, University of Massachusetts Chan Medical School, 
      Worcester, Massachusetts, USA.
FAU - Gao, Xin D
AU  - Gao XD
AD  - RNA Therapeutics Institute, University of Massachusetts Chan Medical School, 
      Worcester, Massachusetts, USA.
FAU - Rodriguez, Tomas
AU  - Rodriguez T
AUID- ORCID: 0000-0002-8724-5427
AD  - RNA Therapeutics Institute, University of Massachusetts Chan Medical School, 
      Worcester, Massachusetts, USA.
FAU - Cheng, Haoyang
AU  - Cheng H
AUID- ORCID: 0000-0003-3313-9853
AD  - RNA Therapeutics Institute, University of Massachusetts Chan Medical School, 
      Worcester, Massachusetts, USA.
FAU - Kelly, Karen
AU  - Kelly K
AD  - RNA Therapeutics Institute, University of Massachusetts Chan Medical School, 
      Worcester, Massachusetts, USA.
FAU - Watts, Jonathan K
AU  - Watts JK
AD  - RNA Therapeutics Institute, University of Massachusetts Chan Medical School, 
      Worcester, Massachusetts, USA.
AD  - Departments of Biochemistry and Molecular Biotechnology, University of 
      Massachusetts Chan Medical School, Worcester, Massachusetts, USA.
AD  - NeuroNexus Institute, University of Massachusetts Chan Medical School, Worcester, 
      Massachusetts, USA.
FAU - Xie, Jun
AU  - Xie J
AD  - Horae Gene Therapy Center, University of Massachusetts Chan Medical School, 
      Worcester, Massachusetts, USA.
AD  - Viral Vector Core, University of Massachusetts Chan Medical School, Worcester, 
      Massachusetts, USA.
AD  - Departments of Microbiology and Physiological Systems, University of 
      Massachusetts Chan Medical School, Worcester, Massachusetts, USA..
AD  - Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan 
      Medical School, Worcester, Massachusetts, USA.
FAU - Gao, Guangping
AU  - Gao G
AD  - Horae Gene Therapy Center, University of Massachusetts Chan Medical School, 
      Worcester, Massachusetts, USA.
AD  - Viral Vector Core, University of Massachusetts Chan Medical School, Worcester, 
      Massachusetts, USA.
AD  - Departments of Microbiology and Physiological Systems, University of 
      Massachusetts Chan Medical School, Worcester, Massachusetts, USA..
AD  - Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan 
      Medical School, Worcester, Massachusetts, USA.
FAU - Wolfe, Scot A
AU  - Wolfe SA
AD  - Departments of Molecular, Cell and Cancer Biology, University of Massachusetts 
      Chan Medical School, Worcester, Massachusetts, USA.
AD  - Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan 
      Medical School, Worcester, Massachusetts, USA.
FAU - Xue, Wen
AU  - Xue W
AD  - RNA Therapeutics Institute, University of Massachusetts Chan Medical School, 
      Worcester, Massachusetts, USA.
AD  - Departments of Molecular, Cell and Cancer Biology, University of Massachusetts 
      Chan Medical School, Worcester, Massachusetts, USA.
AD  - Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan 
      Medical School, Worcester, Massachusetts, USA.
AD  - Program in Molecular Medicine, University of Massachusetts Chan Medical School, 
      Worcester, Massachusetts, USA.
FAU - Sontheimer, Erik J
AU  - Sontheimer EJ
AUID- ORCID: 0000-0002-0881-0310
AD  - RNA Therapeutics Institute, University of Massachusetts Chan Medical School, 
      Worcester, Massachusetts, USA.
AD  - Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan 
      Medical School, Worcester, Massachusetts, USA.
AD  - Program in Molecular Medicine, University of Massachusetts Chan Medical School, 
      Worcester, Massachusetts, USA.
LA  - eng
GR  - R01 GM125797/GM/NIGMS NIH HHS/United States
PT  - Journal Article
DEP - 20220614
PL  - United States
TA  - GEN Biotechnol
JT  - GEN biotechnology
JID - 9918400388506676
PMC - PMC9258002
COIS- H.Z., N.B., P.L., X.D.G., S.A.W., W.X., and E.J.S. are coinventors on patent 
      filings related to this study. G.G. is scientific cofounder, scientific advisor, 
      and equity holder of Voyager Therapeutics, Adrenas Therapeutics, and Aspa 
      Therapeutics. E.J.S. is a cofounder, scientific advisor, and equity holder of 
      Intellia Therapeutics, and a member of the scientific advisory board of Tessera 
      Therapeutics.
EDAT- 2022/07/12 06:00
MHDA- 2022/07/12 06:01
PMCR- 2023/07/06
CRDT- 2022/07/11 03:35
PHST- 2022/03/29 00:00 [received]
PHST- 2022/05/11 00:00 [accepted]
PHST- 2022/07/11 03:35 [entrez]
PHST- 2022/07/12 06:00 [pubmed]
PHST- 2022/07/12 06:01 [medline]
PHST- 2023/07/06 00:00 [pmc-release]
AID - 10.1089/genbio.2022.0015 [pii]
AID - 10.1089/genbio.2022.0015 [doi]
PST - ppublish
SO  - GEN Biotechnol. 2022 Jun 1;1(3):285-299. doi: 10.1089/genbio.2022.0015. Epub 2022 
      Jun 14.