IN UTERO TRANSPLANTATION IN BETA-THALASSEMIA

描述：β地中海贫血是最常见的遗传性疾病之一 并日益全球化。 当前常规 这种使人衰弱的血红蛋白病的治疗方法复杂，昂贵， 并且不能治愈。 造血干细胞（HSC）移植可能 治愈b-地中海贫血，但移植相关的发病率和死亡率是 相当可观 此外，干细胞移植受到缺乏 合适的组织相容性干细胞供体 胎儿测试的出现 现在提供了一个机会，以评估在子宫内治疗， 血红蛋白病以及免疫缺陷病症和代谢性疾病 疾病 子宫内移植有可能增加供体 通过绕过与产后相关的免疫屏障， 移植不匹配的细胞，也将允许治疗 在严重的病理事件发生之前。 它是假设 造血干细胞在子宫内的移植提供了一个永久的来源， 正常的红细胞在B-地中海贫血小鼠模型。 在目标1中， 地中海贫血的严重程度、植入和 供体细胞的分化和血液学的校正 在子宫内移植后小鼠b-地中海贫血的表现将 被定义。 在目标2中，免疫介导的机制在控制 在出生前和出生后的b-地中海贫血患者中HSC植入和分化 将对小鼠进行研究。 在aim 3中，促红细胞生成素在调节 移植到子宫内的HSC的植入和分化将是 研究了 本提案的目标是确定 造血干细胞在小鼠模型中的对照植入 b地中海贫血，并检查移植程序， 在临床试验中的适用性，这种常见的遗传性血液病 disorder.

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.