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: 7086528
• 负责人: GEORGE R BUCHANAN
• 金额: $ 10万
• 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/7086528
• 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，镰状细胞病（SCD）的治疗显着降低了 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。这些进步归功于临床、遗传和分子方面的进步 揭示了 SCD 病理生理学的基本方面。尽管取得了这些进步，SCD 仍然与显着的死亡率和发病率相关。大量数据 自体干细胞骨髓移植已证明对少数人有效 SCD 患者的数量，但早期死亡率、合适供体的可用性以及所涉及的因素 患者选择仍然是限制因素。作为替代方案，SCD 的基因校正可提供 希望能成为广大患者的潜在治疗方法。最近的进展 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有力的理论依据和动力 SCD 的方法。在本提案中，我们解决了成功的三个重要挑战 SCD 的遗传校正。首先，我们开发基于慢病毒的载体用于转导 人类伽马珠蛋白基因。这些载体包含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估。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，我们使用体内评估这些转导的细胞 人/小鼠骨髓移植异种移植模型。获得的临床前数据 这些实验将作为未来临床实施的合理依据 旨在纠正 SCD 基因的基因治疗方案。