PMID- 30533448
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200930
IS  - 2329-0501 (Print)
IS  - 2329-0501 (Electronic)
IS  - 2329-0501 (Linking)
VI  - 11
DP  - 2018 Dec 14
TI  - Pre-clinical Development of a Lentiviral Vector Expressing the Anti-sickling betaAS3 
      Globin for Gene Therapy for Sickle Cell Disease.
PG  - 167-179
LID - 10.1016/j.omtm.2018.10.014 [doi]
AB  - Sickle cell disease (SCD) is caused by a mutation (E6V) in the hemoglobin (Hb) 
      beta-chain that induces polymerization of Hb tetramers, red blood cell deformation, 
      ischemia, anemia, and multiple organ damage. Gene therapy is a potential 
      alternative to human leukocyte antigen (HLA)-matched allogeneic hematopoietic 
      stem cell transplantation, available to a minority of patients. We developed a 
      lentiviral vector expressing a beta-globin carrying three anti-sickling mutations 
      (T87Q, G16D, and E22A) inhibiting axial and lateral contacts in the HbS polymer, 
      under the control of the beta-globin promoter and a reduced version of the beta-globin 
      locus-control region. The vector (GLOBE-AS3) transduced 60%-80% of mobilized 
      CD34(+) hematopoietic stem-progenitor cells (HSPCs) and drove betaAS3-globin 
      expression at potentially therapeutic levels in erythrocytes differentiated from 
      transduced HSPCs from SCD patients. Transduced HSPCs were transplanted in 
      NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ (NSG)-immunodeficient mice to analyze 
      biodistribution, chimerism, and transduction efficiency in bone marrow (BM), 
      spleen, thymus, and peripheral blood 12-14 weeks after transplantation. Vector 
      integration site analysis, performed in pre-transplant HSPCs and post-transplant 
      BM cells from individual mice, showed a normal lentiviral integration pattern and 
      no evidence of clonal dominance. An in vitro immortalization (IVIM) assay showed 
      the low genotoxic potential of GLOBE-AS3. This study enables a phase I/II 
      clinical trial aimed at correcting the SCD phenotype in juvenile patients by 
      transplantation of autologous hematopoietic stem cells (HSC) transduced by 
      GLOBE-AS3.
FAU - Poletti, Valentina
AU  - Poletti V
AD  - Genethon, Evry, France.
FAU - Urbinati, Fabrizia
AU  - Urbinati F
AD  - Department of Microbiology, Immunology and Molecular Genetics, UCLA, Los Angeles, 
      CA, USA.
FAU - Charrier, Sabine
AU  - Charrier S
AD  - Genethon, Evry, France.
FAU - Corre, Guillaume
AU  - Corre G
AD  - Genethon, Evry, France.
FAU - Hollis, Roger P
AU  - Hollis RP
AD  - Department of Microbiology, Immunology and Molecular Genetics, UCLA, Los Angeles, 
      CA, USA.
FAU - Campo Fernandez, Beatriz
AU  - Campo Fernandez B
AD  - Department of Microbiology, Immunology and Molecular Genetics, UCLA, Los Angeles, 
      CA, USA.
FAU - Martin, Samia
AU  - Martin S
AD  - Genethon, Evry, France.
FAU - Rothe, Michael
AU  - Rothe M
AD  - Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
FAU - Schambach, Axel
AU  - Schambach A
AD  - Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
AD  - Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical 
      School, Boston, MA, USA.
FAU - Kohn, Donald B
AU  - Kohn DB
AD  - Department of Microbiology, Immunology and Molecular Genetics, UCLA, Los Angeles, 
      CA, USA.
FAU - Mavilio, Fulvio
AU  - Mavilio F
AD  - Department of Life Sciences, University of Modena and Reggio Emilia, Modena, 
      Italy.
AD  - Paris Descartes University, Imagine Institute, Paris, France.
LA  - eng
PT  - Journal Article
DEP - 20181101
PL  - United States
TA  - Mol Ther Methods Clin Dev
JT  - Molecular therapy. Methods & clinical development
JID - 101624857
PMC - PMC6276308
OTO - NOTNLM
OT  - NSG mice
OT  - gene therapy
OT  - genotoxicity
OT  - hematopoietic stem-progenitor cells
OT  - integration
OT  - lentiviral vector
OT  - sickle cell disease
OT  - stem cell clonality
OT  - xenograft
EDAT- 2018/12/12 06:00
MHDA- 2018/12/12 06:01
PMCR- 2018/11/01
CRDT- 2018/12/12 06:00
PHST- 2018/08/09 00:00 [received]
PHST- 2018/10/29 00:00 [accepted]
PHST- 2018/12/12 06:00 [entrez]
PHST- 2018/12/12 06:00 [pubmed]
PHST- 2018/12/12 06:01 [medline]
PHST- 2018/11/01 00:00 [pmc-release]
AID - S2329-0501(18)30110-4 [pii]
AID - 10.1016/j.omtm.2018.10.014 [doi]
PST - epublish
SO  - Mol Ther Methods Clin Dev. 2018 Nov 1;11:167-179. doi: 
      10.1016/j.omtm.2018.10.014. eCollection 2018 Dec 14.