UNIV OF TX SOUTHWESTERN COMPREHENSIVE MED SICKLE CELL CT

近年来，镰状细胞病（SCD）的治疗显著降低了患者的免疫功能。 镰状细胞危象的频率和持续时间，并大大延长了 患者这些改善是由于临床、遗传和分子方面的进展， 揭示了SCD病理生理学的基本方面。尽管有这些进步，SCD 仍然与显著的死亡率和发病率相关。大量的数据， 自体干细胞骨髓移植已显示对少数人有效 的SCD患者，但早期死亡率，合适的供体的可用性和相关因素 患者选择仍然是限制因素。作为替代方案，SCD的遗传校正提供了 希望对大多数患者来说是一种潜在的治疗方法。研究进展 血红蛋白疾病小鼠模型的开发和基于慢病毒的载体设计 为基因治疗的临床前实施提供了强大的理论基础和动力 接近SCD。在这份提案中，我们解决了成功的三个重要挑战， SCD的遗传校正。首先，我们开发了基于慢病毒的载体，用于转导 人类γ-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评价。其次，我们评估了它们向SCD患者骨髓来源的造血干细胞的转导效率。第三，我们在体内使用 骨髓移植人/小鼠异种移植模型。获得的临床前数据 这些实验结果将作为未来临床实施的合理依据。 基因治疗方案旨在遗传校正SCD。

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.