UNIV OF TX SOUTHWESTERN COMPREHENSIVE MED SICKLE CELL CT

近年来，对镰刀细胞病(SCD)的治疗显著减少了 镰状细胞危机的频率和持续时间，并显著延长了 病人。这些改善归功于临床、遗传和分子方面的进步 揭示了SCD病理生理学的基本方面。尽管有这些进步，但SCD 仍然与显著的死亡率和发病率有关。的海量数据 自体干细胞骨髓移植已证明对少数人有效 SCD患者的早期死亡率、合适供体的可获得性和相关因素 患者的选择仍然是限制因素。作为另一种选择，SCD的基因矫正提供了 对于大多数患者来说，希望是一种潜在的治疗方法。最新的研究进展 小鼠血红蛋白紊乱模型的建立及慢病毒载体的设计 为基因治疗的临床前实施提供了强大的理论基础和动力 SCD的方法。在这项提案中，我们解决了三个成功的挑战 SCD的遗传矫正。首先，我们开发了基于慢病毒的载体来转导 人类的伽马珠蛋白基因。这些载体包括对高水平单拷贝基因表达至关重要的调控元件，并在转基因小鼠和模型细胞系中进行了评估。其次，我们评估了它们对SCD患者骨髓来源的造血干细胞的转导效率。第三，我们在体内评估这些转导细胞使用 人/小鼠异种骨髓移植模型的建立。获得的临床前数据 这些实验结果将作为今后临床实施的合理依据 旨在对SCD进行基因矫正的基因治疗方案。

In recent years, treatments for Sickle Cell Disease (SCD) have significantly decreased the frequency and duration of sickle cell crises and significantly lengthened the life expectancy of patients. These improvements have been due to clinical, genetic and molecular advances that have revealed basic aspects of the pathophysiology of SCD. In spite of these advances, SCD remains associated with significant mortality and morbidity. The large body of data for autologous stem cell bone marrow transplantation has shown it to be effective for a minority of patients with SCD, but early mortality, the availability of suitable donors and factors involved in patient selection remain limiting factors. As an alternative, genetic correction of SCD offers hope as a potential curative approach for the majority of patients. Recent progress in the development of mouse models of hemoglobin disorders and in lentivirus-based vector design have provided strong rationale and impetus for preclinical implementation of gene therapy approaches for SCD. In this proposal, we address three important challenges to the successful genetic correction of SCD. First, we develop lentivirus-based vectors for the transduction of human gamma-globin genes. These vectors include regulatory elements that are critical for high-level single copy gene expression and are evaluated both in transgenic mice and model cell lines. Second, we evaluate their transduction efficiency into bone marrow-derived hematopoietic stem cells from SCD patients. And third, we evaluate these transduced cells in vivo using a human/mouse xenograft model of bone marrow transplantation. The preclinical data obtained from these experiments will serve as the rational basis for the implementation of future clinical gene therapy protocols aimed at the genetic correction of SCD.