UNIV OF TX SOUTHWESTERN COMPREHENSIVE MED SICKLE CELL CT

德克萨斯大学西南综合医学镰状细胞 CT

• 批准号: 6504810
• 负责人: GEORGE R BUCHANAN
• 金额: $ 158.08万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6504810
• 关键词: clinical research; cooperative study; sickle cell anemia

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.

近年来，镰状细胞疾病（SCD）的治疗已大大降低 镰状细胞危机的频率和持续时间，并显着延长了预期寿命 患者。这些改善是由于临床，遗传和分子进步所致 已经揭示了SCD病理生理学的基本方面。尽管有这些进步，SCD 仍然与重大死亡率和发病率有关。大量数据 自体干细胞骨髓移植表明它对少数族裔有效 患有SCD但早期死亡率的患者，合适的供体的可用性和涉及的因素 在患者中，选择仍然是限制因素。作为替代方案，SCD的遗传校正提供了 希望作为大多数患者的潜在治疗方法。最近的进步 开发血红蛋白疾病的小鼠模型和基于慢病毒的矢量设计 为临床前实施基因治疗提供了强大的理由和动力 SCD的方法。在此提案中，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向量，以转导 人γ-球蛋白基因。这些向量包括对高级单拷贝基因表达至关重要的调节元件，并在转基因小鼠和模型细胞系中进行了评估。其次，我们评估了它们的转导效率，来自SCD患者的骨髓来源造血干细胞。第三，我们使用A在体内评估了这些转导的细胞 人/小鼠异种移植模型的骨髓移植模型。获得的临床前数据 从这些实验中将成为实施未来临床的合理基础 旨在SCD遗传校正的基因治疗方案。