No evidence for cell activation or brain vaso-occlusion with plerixafor mobilization in sickle cell mice
Introduction
Sickle cell disease (SCD) is caused by a single nucleotide base change in the β-globin gene and is thus an excellent candidate for gene therapy. In fact, gene therapy for SCD is currently in active trials, but collection of hematopoietic progenitor cells (HPCs) safely and effectively remains a challenge. Granulocyte colony stimulating factor (G-CSF), the drug used most commonly for collecting HPC, can cause life-threatening vaso-occlusion in SCD, including multi-organ failure [1]. Bone marrow harvest requires general anesthesia and multiple hip bone punctures. Plerixafor is an inhibitor of the CXCR4 chemokine receptor on HPC, interfering with its binding to SDF-1 (CXCL12) on bone marrow stroma. Plerixafor alone, without concomitant G-CSF, may have excellent mobilization efficacy in SCD patients, as demonstrated by a clinical trial showing safety and efficacy of mobilization with plerixafor alone was superior to G-CSF in splenectomized β-thalassemia patients [2]. As pre-clinical data in support of a clinical trial in SCD patients studying plerixafor mobilization (NCT02193191), we administered plerixafor to SCD mice to assess HPC mobilization; platelet, endothelial, and neutrophil activation; and brain vaso-occlusion.
Section snippets
Sickle mice
All mouse experiments were approved by the NYBC and Einstein Institutional Animal Care and Use Committee and performed between July 2014 and February 2015. Male and female 3–6 month old SS Berkeley (stock number 003342, The Jackson Laboratory, Farmington, CT) or SS Townes mice (stock number 013071, The Jackson Laboratory, Farmington, CT) were used for all experiments.
A cohort of Berkeley mice at Einstein (n = 8: 4 plerixafor, 2 G-CSF, 2 saline) was used for the initial 4 experiments performed,
Results and discussion
Plerixafor and G-CSF were absorbed as evidenced by expected changes in WBC and platelet counts with treatment compared to saline. CBC showed the mean WBC and platelet counts of both plerixafor and G-CSF groups to be significantly different from saline (Fig. 1A), but the WBC differential was significantly different (in % and absolute numbers of neutrophils and lymphocytes) from saline only in the G-CSF group (Fig. 1B).
Both plerixafor and G-CSF significantly mobilized HPC subsets. The percentages
Authorship contributions and disclosure of conflicts of Interest
EC: conducted the study and analyzed data.
CB: designed the study, analyzed data, and wrote the manuscript.
MC: conducted the mouse imaging studies.
KY: analyzed data and reviewed the manuscript.
MN: designed the study and reviewed the manuscript.
HB: designed the study and reviewed the manuscript.
PAS: designed the study, analyzed data, and wrote the manuscript.
The authors report no relevant conflict of interests.
Acknowledgments
The authors are grateful to Dr. Farid Boulad, Dr. Tsiporah Shore, and Donna Offenbacker for providing plerixafor for the study, Sandra Suzuka for providing the Berkeley mice, and Petra Pham for flow cytometry assistance.
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2018, Experimental HematologyCitation Excerpt :Plerixafor does not induce leukocytosis to the same extent as G-CSF. In an SCD mouse model, plerixafor has been shown to mobilize HSC subsets effectively without neutrophil or endothelial activation and with lower total white blood cells and neutrophil counts than in G-CSF-treated mice [237]. It is currently being tested in humans with severe SCD [112,238], including several patients currently enrolled in the HGB-206 trial [112].
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2018, Seminars in HematologyCitation Excerpt :The requirement to cease HU therapy would support the commencement of a transfusion regimen before mobilization, collection, and GT/GE. Plerixafor has been compared to G-CSF in a SCD mouse model, and results showed effective mobilization of HSC subsets, without neutrophil or endothelial activation, and with lower total WBC and neutrophil counts compared to G-CSF-treated mice [114]. Plerixafor has now been tested in 4 small clinical studies of SCD patients (Table).
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