THERAPEUTIC ROLES OF HEALTHY DONOR HUMAN LIVER SINUSOIDAL ENDOTHELIAL CELLS (LSEC), BONE MARROW OR CORD BLOOD-DERIVED CELLS IN HEMOPHILIA A

  • 3 Years 2009/2012
  • 125.400€ Total Award
New approaches to cure hemophilia A, where factor VIII is deficient, require insights into cell compartments capable of producing FVIII. Recently, we demonstrated that liver sinusoidal endothelial cells (LSEC) produce and secrete FVIII, although not exclusively. We have also found that mice deficient for FVIII can be cured by reconstitution with healthy wild-type bone marrow (BM), indicating that bone marrow-derived cells, of hematopoietic, mesenchymal or even endothelial origin, can produce and secrete FVIII. Based on these findings in mice, we propose that human LSEC, cord blood cells, and bone marrow cells may be suitable sources of FVIII production to be used for cell replacement therapy as a treatment for hemophilia A. To advance opportunities for cell and gene therapies in hemophilia A and for identifying additional cell sources of FVIII, we intend to explore whether replacement of liver endothelium and bone marrow in Hemophilia A mice with healthy human cells will provide therapeutic correction. We propose studies of human cells in hemophilia mice in the NOD/SCID background, which permits successful engraftment of human cells. In early studies, we determined that cells in the mononuclear and stromal cell fractions from human bone marrow express FVIII at the RNA level. To explore if these bone marrow cells or cord blood cells could produce FVIII, we will develop studies in cell culture and in hemophilia A mice. We will transplant human bone marrow or cord blood cells in sublethally-irradiated NOD/SCID Hemophilia A mice and we expect to see that bone marrow reconstitution will correct the bleeding phenotype in these mice. Subsequently, we will explore the possibility of improving therapeutic correction, if necessary, through genetic modification of cells to increase FVIII expression.

Scientific Publications

Il tuo browser non è più supportato da Microsoft, esegui l'upgrade a Microsoft Edge per visualizzare il sito.