PMID- 35922667
OWN - NLM
STAT- MEDLINE
DCOM- 20220822
LR  - 20220921
IS  - 1546-170X (Electronic)
IS  - 1078-8956 (Linking)
VI  - 28
IP  - 8
DP  - 2022 Aug
TI  - CRISPR-Cas9-mediated gene editing of the BCL11A enhancer for pediatric beta(0)/beta(0) 
      transfusion-dependent beta-thalassemia.
PG  - 1573-1580
LID - 10.1038/s41591-022-01906-z [doi]
AB  - Gene editing to disrupt the GATA1-binding site at the +58 BCL11A erythroid 
      enhancer could induce gamma-globin expression, which is a promising therapeutic 
      strategy to alleviate beta-hemoglobinopathy caused by HBB gene mutation. In the 
      present study, we report the preliminary results of an ongoing phase 1/2 trial 
      (NCT04211480) evaluating safety and efficacy of gene editing therapy in children 
      with blood transfusion-dependent beta-thalassemia (TDT). We transplanted BCL11A 
      enhancer-edited, autologous, hematopoietic stem and progenitor cells into two 
      children, one carrying the beta(0)/beta(0) genotype, classified as the most severe type 
      of TDT. Primary endpoints included engraftment, overall survival and incidence of 
      adverse events (AEs). Both patients were clinically well with multilineage 
      engraftment, and all AEs to date were considered unrelated to gene editing and 
      resolved after treatment. Secondary endpoints included achieving transfusion 
      independence, editing rate in bone marrow cells and change in hemoglobin (Hb) 
      concentration. Both patients achieved transfusion independence for >18 months 
      after treatment, and their Hb increased from 8.2 and 10.8 g dl(-1) at screening 
      to 15.0 and 14.0 g dl(-1) at the last visit, respectively, with 85.46% and 89.48% 
      editing persistence in bone marrow cells. Exploratory analysis of single-cell 
      transcriptome and indel patterns in edited peripheral blood mononuclear cells 
      showed no notable side effects of the therapy.
CI  - (c) 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
FAU - Fu, Bin
AU  - Fu B
AUID- ORCID: 0000-0002-3119-7497
AD  - Xiangya Hospital, Central South University, Hunan, China. fu.bin@csu.edu.cn.
FAU - Liao, Jiaoyang
AU  - Liao J
AUID- ORCID: 0000-0002-0443-563X
AD  - Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai 
      Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School 
      of Life Sciences, East China Normal University, Shanghai, China.
FAU - Chen, Shuanghong
AU  - Chen S
AD  - Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai 
      Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School 
      of Life Sciences, East China Normal University, Shanghai, China.
FAU - Li, Wei
AU  - Li W
AUID- ORCID: 0000-0003-3512-7055
AD  - Bioray Laboratories Inc., Shanghai, China.
FAU - Wang, Qiudao
AU  - Wang Q
AD  - Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai 
      Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School 
      of Life Sciences, East China Normal University, Shanghai, China.
FAU - Hu, Jian
AU  - Hu J
AD  - Xiangya Hospital, Central South University, Hunan, China.
FAU - Yang, Fei
AU  - Yang F
AD  - Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai 
      Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School 
      of Life Sciences, East China Normal University, Shanghai, China.
FAU - Hsiao, Shenlin
AU  - Hsiao S
AD  - Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai 
      Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School 
      of Life Sciences, East China Normal University, Shanghai, China.
FAU - Jiang, Yanhong
AU  - Jiang Y
AD  - Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai 
      Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School 
      of Life Sciences, East China Normal University, Shanghai, China.
FAU - Wang, Liren
AU  - Wang L
AD  - Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai 
      Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School 
      of Life Sciences, East China Normal University, Shanghai, China.
FAU - Chen, Fangping
AU  - Chen F
AD  - Xiangya Hospital, Central South University, Hunan, China.
FAU - Zhang, Yuanjin
AU  - Zhang Y
AD  - Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences 
      and School of Life Sciences, East China Normal University, Shanghai, China.
FAU - Wang, Xin
AU  - Wang X
AUID- ORCID: 0000-0001-8079-8638
AD  - Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences 
      and School of Life Sciences, East China Normal University, Shanghai, China.
FAU - Li, Dali
AU  - Li D
AUID- ORCID: 0000-0002-0046-8493
AD  - Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai 
      Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School 
      of Life Sciences, East China Normal University, Shanghai, China. 
      dlli@bio.ecnu.edu.cn.
AD  - Bioray Laboratories Inc., Shanghai, China. dlli@bio.ecnu.edu.cn.
FAU - Liu, Mingyao
AU  - Liu M
AUID- ORCID: 0000-0001-7339-5048
AD  - Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai 
      Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School 
      of Life Sciences, East China Normal University, Shanghai, China. 
      myliu@bio.ecnu.edu.cn.
AD  - Bioray Laboratories Inc., Shanghai, China. myliu@bio.ecnu.edu.cn.
FAU - Wu, Yuxuan
AU  - Wu Y
AUID- ORCID: 0000-0002-9155-9883
AD  - Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai 
      Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School 
      of Life Sciences, East China Normal University, Shanghai, China. 
      yxwu@bio.ecnu.edu.cn.
LA  - eng
SI  - ClinicalTrials.gov/NCT04211480
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220804
PL  - United States
TA  - Nat Med
JT  - Nature medicine
JID - 9502015
RN  - 0 (BCL11A protein, human)
RN  - 0 (Repressor Proteins)
RN  - 0 (beta-Globins)
RN  - 0 (gamma-Globins)
SB  - IM
MH  - CRISPR-Cas Systems/genetics
MH  - Child
MH  - *Gene Editing/methods
MH  - Humans
MH  - Leukocytes, Mononuclear/metabolism
MH  - Repressor Proteins/genetics
MH  - beta-Globins/genetics
MH  - *beta-Thalassemia/genetics/therapy
MH  - gamma-Globins/genetics
EDAT- 2022/08/04 06:00
MHDA- 2022/08/23 06:00
CRDT- 2022/08/03 23:31
PHST- 2021/09/12 00:00 [received]
PHST- 2022/06/17 00:00 [accepted]
PHST- 2022/08/04 06:00 [pubmed]
PHST- 2022/08/23 06:00 [medline]
PHST- 2022/08/03 23:31 [entrez]
AID - 10.1038/s41591-022-01906-z [pii]
AID - 10.1038/s41591-022-01906-z [doi]
PST - ppublish
SO  - Nat Med. 2022 Aug;28(8):1573-1580. doi: 10.1038/s41591-022-01906-z. Epub 2022 Aug 
      4.