Cyp7b1-inhibiting azoles as novel enhancers of hematopoietic stem and progenitor cell mobilization

Mobilized hematopoietic stem and progenitor cells (HSPCs) are essential for transplantation-based therapies, including curative gene therapies for sickle cell disease (SCD). While granulocyte colony-stimulating factor (G-CSF, filgrastim) remains the standard mobilization agent, many patients respond inadequately, and it can trigger life-threatening vaso-occlusive crises in SCD. The CXCR4 antagonist AMD3100 (plerixafor) is routinely combined with G-CSF for non-SCD settings but is ineffective as a single agent in SCD, underscoring the urgent need for alternative strategies. We previously identified 27-hydroxycholesterol (27HC) as a physiological inducer of HSPC mobilization during pregnancy. Here, we show that exogenous 27HC enhances AMD3100-induced HSPC mobilization in mice, either alone or with G-CSF. Because 27HC is metabolized by the enzyme Cyp7b1, we tested whether pharmacological Cyp7b1 inhibition could mimic this effect. Treatment with clotrimazole, an antifungal and Cyp7b1 inhibitor, significantly enhanced AMD3100-induced HSPC mobilization in wild-type, SCD, and humanized mice. Importantly, intravenous administration of voriconazole, a clinically approved systemic antifungal with Cyp7b1-binding activity, similarly augmented AMD3100-induced HSPC mobilization in wild-type and SCD mice without altering steady-state hematopoiesis. These findings establish Cyp7b1-inhibiting azoles as novel and clinically relevant enhancers of HSPC mobilization, particularly for SCD patients who cannot safely receive G-CSF but require robust HSPC yields for gene therapy. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/682145v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1fddaaforg.highwire.dtl.DTLVardef@12036f4org.highwire.dtl.DTLVardef@1f8010aorg.highwire.dtl.DTLVardef@10c4aff_HPS_FORMAT_FIGEXP M_FIG C_FIG