Rapid and Efficient Mobilization of Murine Hematopoietic Stem and Progenitor Cells with Nox-A12, a New Spiegelmers®-Based CXCR4/SDF-1(CXCL12) Antagonist

Abstract 2995

Mobilization of hematopoietic stem cells (HSCs) and progenitor cells (HPCs) is important in many hematological therapies. However, up to 30% of the patients respond poorly to standard granulocyte colony-stimulating factor (G-CSF) treatment, highlighting the need for more effective mobilizing strategies. The CXCR4/stromalcell-derived factor 1 (SDF-1) axis plays a crucial role in the interaction between HSCs and the marrow niche and is involved in HSC mobilization. NOX-A12 is a structured mirror-image RNA oligonucleotide, a so-called Spiegelmer®, that was identified to bind SDF-1 thereby inhibiting its activity with subnanomolar IC50. HSC/HPC mobilization by NOX-A12 was examined in the mouse. Single NOX-A12 administration induced reversible mobilization of HSC/HPC populations within a few hours. NOX-A12 synergized with G-CSF to strongly enhance HSC/HPC mobilization. In particular, the progenitor compartment mobilized by single NOX-A12 administration contained more differentiated short-term HSCs (ST-HSCs), and combined administration of NOX-A12 and G-CSF mobilized a significantly higher proportion of primitive and more potent murine long-term repopulating cells that successfully engrafted primary and secondary lethally-irradiated recipients. These results characterize NOX-A12 as a potent HSCs/HPCs mobilizing therapeutic in mammals and suggest its clinical potential.