No evidence for cell activation or brain vaso-occlusion with plerixafor mobilization in sickle cell mice

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Abstract

Gene therapy for sickle cell disease is currently in active trials. Collecting hematopoietic progenitor cells safely and effectively is challenging, however, because granulocyte colony stimulating factor, the drug used most commonly for mobilization, can cause life-threatening vaso-occlusion in patients with sickle cell disease, and bone marrow harvest requires general anesthesia and multiple hip bone punctures. Plerixafor is an inhibitor of the CXCR4 chemokine receptor on hematopoietic progenitor cells, blocking its binding to SDF-1 (CXCL12) on bone marrow stroma. In support of a clinical trial in patients with sickle cell disease of plerixafor mobilization (NCT02193191), we administered plerixafor to sickle cell mice and found that it mobilizes hematopoietic progenitor cells without evidence of concomitant cell activation or brain vaso-occlusion.

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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