Mobilization Test of BM Progenitor Cells With Plerixafor / AMD3100: Controlled Parallel Group Comparison Between Diabetic and Non Diabetic Subjects

Scientific background. Diabetes mellitus is associated with an increased prevalence and incidence of cardiovascular diseases. It is believed that the high cardiovascular risk in diabetes is attributable to the adverse effects of glucotoxicity and lipotoxicity on endothelial cells. Recent data indicate that endothelial repair mechanisms play an important role in determining the integrity of the endothelium and thus the global health of the cardiovascular system. Data from our research group demonstrated that the cells involved in endothelial regeneration and neo-angiogenesis (including CD34+ cells and endothelial progenitor cells, EPC) are reduced in number and dysfunctional in patients with diabetes mellitus. EPC belong to the CD34+ cell population and are defined based on the co-expression of endothelial-lineage markers, such as VEGF receptor 2 (VEGFR2 or KDR). These cells are further impaired in diabetic patients with cardiovascular disease. It is believed that these changes represent one of the causes of cardiovascular damage in diabetes.

The mechanisms underlying the decrease of EPC and other progenitor cells in diabetes are not fully understood. Normally, EPC reside in the bone marrow and their circulating levels in peripheral blood are very low. In response to ischemic injury or vascular damage, EPC are mobilized from the bone marrow to peripheral blood. Data obtained in experimental models of diabetes mellitus indicate a defect in EPC mobilization from the bone marrow to the peripheral circulation in response to ischemia, which results in an impairment of the post-ischemic neo-angiogenetic processes. Similar experimental results were obtained by different research groups. Our data also show that experimental diabetes reduces the marrow response to exogenous mobilizing agents such as G-CSF and SCF. Other clinical data in humans from our and other research groups confirm the hypothesis of a defect in the bone marrow of patients with diabetes mellitus. In particular, diabetes causes profound alterations of the bone marrow microenvironment associated with microangiopathy and alteration of the stem cells niche. These results confirm a study in the mouse model of type 1 diabetes, in which it was for the first time identified a specific form of microangiopathy causing depletion of CD34+ cells and EPC in the bone marrow.

As a consequence of this bone marrow damage, our research group has recently shown that the mobilization of CD34+ cells and EPC phenotypes is profoundly defective in patients with type 1 and 2 diabetes mellitus.

To reach this conclusion, the investigators used a test of bone marrow reserve by administering low dose human recombinant G-CSF (Filgrastim). The study showed that a sub-maximal marrow stimulation is able to highlight differences between diabetics and non-diabetics and is absolutely safe, since there have been no significant side effects. In a hematology context, it was also previously shown that diabetes is a factor predictive of "poor mobilization" exposing patients to an increased risk of failing stem cell collection for autologous stem cell transplantation.

From a functional/mechanistic standpoint, it has been demonstrated that an impairment of the CXCL12/CXCR4 axis probably contributes to the lack of mobilization of bone marrow stem/progenitor cells associated with diabetes. The drug AMD3100 / plerixafor (Mozobil ®) is a direct antagonist of CXCR4 and inhibits the cellular signal keeping stem / progenitor cells within the bone marrow. For this reason, AMD3100 / Plerixafor is rapidly effective for the mobilization of bone marrow stem cells. From an experimental point of view, it was observed that diabetic animals, although not responsive to mobilization induced by ischemia and G-CSF, are responsive to mobilization induced by AMD3100 / Plerixafor. Mozobil is currently approved in Italy for stem cell mobilization in patients with multiple myeloma or lymphoma for the purpose of auto-transplantation, in combination with G-CSF, in poorly mobilizing patients (see SmPC). At this stage, the effectiveness of Mozobil in inducing mobilization of stem / progenitor cells in diabetic patients has not yet been tested.