GENE THERAPY FOR SICKLE CELL ANEMIA

该项目的总体目标是确定镰状细胞病如何改变造血干细胞群的特征以及造血对慢性溶血的反应方式。 在过去的一年里，我们完成了关于“循环细胞因子反应和镰状细胞性贫血的红细胞生成水平”的研究（Am. J of Hematology 60：105-115），并将我们的注意力集中在SS疾病中循环LTC-IC（长期培养-起始细胞）和克隆源性干细胞的行为上。 我们的研究结果表明，SS贫血的特点是不同程度的动员干细胞和祖细胞（平均约10倍）。 发现检查的所有祖细胞都增加（主要在HbF升高的患者中）的事实表明SS疾病的病理作用不仅限于红系谱系，而且影响整个干细胞区室。 对单个SS患者循环LTC-IC和CFC值的相关性分析证实，观察到的变化不是隔室特异性的。从对单个SS患者亚组进行的水平研究中获得了共同潜在机制的额外证据。这些研究表明，所有祖细胞的数量随时间显著波动，但以相关方式。 发现大多数循环LTC-IC是静止的，但比正常个体更快地被招募到循环中。 目前的研究结果提供的证据表明，SS贫血与循环干细胞和祖细胞耗竭的任何迹象无关。 相反，在镰状细胞性贫血中，这些细胞以增加的数量循环，并且可能特别适合作为基因转移的靶点。

The overall goal of this project is to determine how sickle cell disease may alter the characteristics of the hematopoietic stem cell populations and the way how hematopoiesis responds to the chronic hemolysis. Over the past year we completed the study on "Circulating Cytokines Response and the level of Erythropoiesis in Sickle Cell Anemia" (Am. J of Hematology 60:105-115) and focused our attention on the behavior of circulating LTC-IC ( Long term culture -Initiating cells ) and clonogenic stem cells in SS disease . Our results show that the SS anemia is characterized by the various degree of mobilization of stem and progenitor cells (on average ,approximately 10-fold). The fact that all progenitors examined were found to be increased ( mainly in patients with elevated HbF) showed that the pathological effect of SS disease is not restricted to erythroid lineage only, but affects the entirety of stem cell compartment. Correlation analysis of the circulating LTC-IC and CFC values for individual SS patients confirmed that the changes seen were not compartment specific Additional evidence of a common underlying mechanism was obtained from a horizontal studies performed on a subset of individual SS patients .These studies showed that the numbers of all progenitors fluctuated markedly over time but in correlated fashion . The majority of circulating LTC-IC were found to be quiescent, but were recruited into the cycle more rapidly than thus of normal individuals. The present findings provide evidence that SS anemia is not associated with any signs of exhaustion of circulating stem and progenitors cells. On the contrary, that these cells, in sickle cell anemia circulate in increased numbers and may be particulary suited as a target for gene transfer.