From coagulation to angiogenesis: new roles for FVIII in endothelial functionality

Hemophilia A (HA) is a rare disorder caused by the absence or the dysfunction of FVIII protein. Based on its residual activity, there are several degrees of severity. In particular, in severe HA patients, spontaneous bleeding episodes frequently occur without any clear cause. Standard therapies are ineffective in preventing the bleedings, therefore arthropathy development remains one of the main complications in the management of HA patients. The impairment of vessel stability in HA is not understood and the impact of this defect related to the absence or low activity of FVIII as never been explored. Our studies show that, in severe HA patients, the endothelium (EC) is more permeable and less functional than healthy controls, suggesting a role of FVIII in vessel stability. The EC fragility was attenuated after transduction of HA-ECs with a lentiviral vector (LV) expressing FVIII, suggesting its extra-coagulative role in enhancing vessel stability. Therefore, to elucidate the extra-coagulative role of FVIII, we will engineer healthy EC to generate mutated cells and analyze gene expression, epigenetic status and protein secretion profile in HA and healthy ECs. These cells will be corrected using LV expressing FVIII under the control of the naïve promoter. Finally, we will investigate whether restored FVIII can improve vessel stability in addition to the bleeding defect in a HA mouse models. Therefore, the study of the extra-coagulative role of FVIII can offer new strategies for the management of HA patients and can pave the way for the development of combined cell and gene therapy strategies for a more efficient treatment of HA.