PMID- 33646305
OWN - NLM
STAT- MEDLINE
DCOM- 20210531
LR  - 20231102
IS  - 2473-9537 (Electronic)
IS  - 2473-9529 (Print)
IS  - 2473-9529 (Linking)
VI  - 5
IP  - 5
DP  - 2021 Mar 9
TI  - Single-dose MGTA-145/plerixafor leads to efficient mobilization and in vivo 
      transduction of HSCs with thalassemia correction in mice.
PG  - 1239-1249
LID - 10.1182/bloodadvances.2020003714 [doi]
AB  - We have developed an in vivo hemopoietic stem cell (HSC) gene therapy approach 
      without the need for myelosuppressive conditioning and autologous HSC 
      transplantation. It involves HSC mobilization and IV injection of a 
      helper-dependent adenovirus HDAd5/35++ vector system. The current mobilization 
      regimen consists of granulocyte colony-stimulating factor (G-CSF) injections over 
      a 4-day period, followed by the administration of plerixafor/AMD3100. We tested a 
      simpler, 2-hour, G-CSF-free mobilization regimen using truncated GRO-beta (MGTA-145; 
      a CXCR2 agonist) and plerixafor in the context of in vivo HSC transduction in 
      mice. The MGTA-145+plerixafor combination resulted in robust mobilization of 
      HSCs. Importantly, compared with G-CSF+plerixafor, MGTA-145+plerixafor led to 
      significantly less leukocytosis and no elevation of serum interleukin-6 levels 
      and was thus likely to be less toxic. With both mobilization regimens, after in 
      vivo selection with O6-benzylguanine (O6BG)/BCNU, stable GFP marking was achieved 
      in >90% of peripheral blood mononuclear cells. Genome-wide analysis showed 
      random, multiclonal vector integration. In vivo HSC transduction after 
      mobilization with MGTA-145+plerixafor in a mouse model for thalassemia resulted 
      in >95% human gamma-globin+ erythrocytes at a level of 36% of mouse beta-globin. 
      Phenotypic analyses showed a complete correction of thalassemia. The gamma-globin 
      marking percentage and level were maintained in secondary recipients, further 
      demonstrating that MGTA145+plerixafor mobilizes long-term repopulating HSCs. Our 
      study indicates that brief exposure to MGTA-145+plerixafor may be advantageous as 
      a mobilization regimen for in vivo HSC gene therapy applications across diseases, 
      including thalassemia and sickle cell disease.
CI  - (c) 2021 by The American Society of Hematology.
FAU - Li, Chang
AU  - Li C
AD  - Division of Medical Genetics, Department of Medicine, University of Washington, 
      Seattle, WA.
FAU - Goncalves, Kevin A
AU  - Goncalves KA
AD  - Magenta Therapeutics, Cambridge, MA.
FAU - Rasko, Tamas
AU  - Rasko T
AD  - AG "Mobile DNA Lab," Max Delbruck Center for Molecular Medicine, Berlin-Buch, 
      Germany.
FAU - Pande, Amit
AU  - Pande A
AD  - AG "Mobile DNA Lab," Max Delbruck Center for Molecular Medicine, Berlin-Buch, 
      Germany.
FAU - Gil, Sucheol
AU  - Gil S
AD  - Division of Medical Genetics, Department of Medicine, University of Washington, 
      Seattle, WA.
FAU - Liu, Zhinan
AU  - Liu Z
AD  - Division of Medical Genetics, Department of Medicine, University of Washington, 
      Seattle, WA.
FAU - Izsvak, Zsuzsanna
AU  - Izsvak Z
AD  - AG "Mobile DNA Lab," Max Delbruck Center for Molecular Medicine, Berlin-Buch, 
      Germany.
FAU - Papayannopoulou, Thalia
AU  - Papayannopoulou T
AD  - Division of Hematology, Department of Medicine, University of Washington, 
      Seattle, WA.
FAU - Davis, John C
AU  - Davis JC
AD  - Magenta Therapeutics, Cambridge, MA.
FAU - Kiem, Hans-Peter
AU  - Kiem HP
AD  - Fred Hutchinson Cancer Research Center, Seattle, WA; and.
AD  - Division of Medical Oncology, Department of Medicine, and.
AD  - Department of Pathology, University of Washington, Seattle, WA.
FAU - Lieber, Andre
AU  - Lieber A
AD  - Division of Medical Genetics, Department of Medicine, University of Washington, 
      Seattle, WA.
AD  - Department of Pathology, University of Washington, Seattle, WA.
LA  - eng
GR  - R01 AI174304/AI/NIAID NIH HHS/United States
GR  - R01 HL130040/HL/NHLBI NIH HHS/United States
GR  - R01 HL141781/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood Adv
JT  - Blood advances
JID - 101698425
RN  - 0 (Benzylamines)
RN  - 0 (Cyclams)
RN  - 0 (Heterocyclic Compounds)
RN  - S915P5499N (plerixafor)
SB  - IM
MH  - Animals
MH  - Benzylamines
MH  - Cyclams
MH  - Hematopoietic Stem Cell Mobilization
MH  - *Heterocyclic Compounds/pharmacology
MH  - Leukocytes, Mononuclear
MH  - Mice
MH  - *Thalassemia/drug therapy
PMC - PMC7948287
COIS- Conflict-of-interest disclosure: A.L. and H-P.K. are scientific cofounders of 
      Ensoma, Inc. Z.I. is a cofounder of MDCell, a Helmholtz Innovation Laboratory. 
      K.A.G. and J.C.D. are employees and shareholders of Magenta Therapeutics. The 
      remaining authors declare no competing financial interests.
EDAT- 2021/03/02 06:00
MHDA- 2021/06/01 06:00
PMCR- 2021/03/01
CRDT- 2021/03/01 12:13
PHST- 2020/10/29 00:00 [received]
PHST- 2021/01/12 00:00 [accepted]
PHST- 2021/03/01 12:13 [entrez]
PHST- 2021/03/02 06:00 [pubmed]
PHST- 2021/06/01 06:00 [medline]
PHST- 2021/03/01 00:00 [pmc-release]
AID - S2473-9529(21)00147-6 [pii]
AID - 2020/ADV2020003714 [pii]
AID - 10.1182/bloodadvances.2020003714 [doi]
PST - ppublish
SO  - Blood Adv. 2021 Mar 9;5(5):1239-1249. doi: 10.1182/bloodadvances.2020003714.