IN UTERO TRANSPLANTATION IN BETA-THALASSEMIA

点击翻译按钮获取中文摘要

DESCRIPTION: Beta-thalassemia is one of the most common inherited disorders in man and has an increasingly global distribution. Current conventional therapies for this debilitating hemoglobinopathy are complicated, expensive, and are not curative. Hematopoietic stem cell (HSC) transplantation may cure b-thalassemia, but transplant-related morbidity and mortality is substantial. Additionally, stem cell transplantation is limited by the lack of suitable histocompatible stem cell donors. The advent of fetal testing now provides an opportunity to evaluate in utero therapy for hemoglobinopathies as well as immunodeficiency disorders and metabolic diseases. Transplantation in utero has the potential to increase the donor pool by circumventing the immunological barriers associated with post-natal transplantation of mismatched cells, and would also allow for treatment before the onset of serious pathological episodes. It is hypothesized that engraftment of hematopoietic stem cells in utero provides a permanent source of normal red blood cells in murine models of b-thalassemia. In aim 1, the relationships between the severity of b-thalassemia, engraftment and differentiation of donor cells and correction of the hematologic manifestations of murine b-thalassemia after in utero transplantation will be defined. In aim 2, the role of immune-mediated mechanisms in the control of HSC engraftment and differentiation in pre- and post-natal b-thalassemic mice will be studied. In aim 3, the role of erythropoietin in regulation of engraftment and differentiation of HSC transplanted in utero will be investigated. The goal of this proposal is to determine the mechanisms that control engraftment of hematopoietic stem cells in murine models of b-thalassemia and to examine transplant procedures that have potential applicability in clinical trials for this common heritable hematologic disorder.