PRECLINICAL ASSESSMENT OF A GENE THERAPY APPROACH OF B THALASSEMIA

Thalassemias are genetic diseases caused by mutations in the genes coding for hemoglobin. They represent the most common monogenic disorders worldwide, affecting thousands of newborn annually. The most severe form of thalassemia, known as ß-thalassemia major or Cooley’s anemia, leadsto a profound anemia and to death in the first year of life, unless a regular transfusion regimen is complied. So far, the only curative treatment is represented by bone marrow transplantation from a compatible donor, but it is available to less than 30% of the patients. The genetic correction of this disease requires integration of the ß-globin gene in the hematopoietic stem cells and regulation of its expression specifically in the red blood cells. The recent development of a novel gene transfer system, the lentiviral vectors (LVs) and the optimization of culture conditions and transduction protocols significantly improved the efficiency of gene transfer into stem cells, leading to the synthesis of therapeutic levels of vector-derived ß-globin in murine and human thalassemic cells. The aim of this project is to provide efficacy and safety data of a gene therapy approach to ß-thalassemia in order to evaluate the feasibility of a future clinical translation. We will improve our current LVs expressing ß-globin to test their therapeutic potential in murine models of thalassemia, and in human cells, obtained from of thalassemic patients and transplanted in immunodeficient mice. Additionally, we will test the efficacy and safety of a truncated form of the erythropoietin receptor in selecting and expanding the corrected stem cells after transplantation. If successful, this study is expected to provide a rational basis for designing a gene therapy strategy for ß-thalassemia.