Gene therapy for acute promyelocytic leukemia

急性早幼粒细胞白血病的基因治疗

• 批准号: 7057670
• 负责人: SIMONE V WARD
• 金额: $ 5.04万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7057670
• 关键词: DNA directed RNA polymerase; Lentivirus; RNA interference; acute myelogenous leukemia; biotechnology; bone marrow transplantation; chimeric proteins; disease /disorder model; flow cytometry; gene induction /repression; gene therapy; green fluorescent proteins; laboratory mouse; methylguanine DNA methyltransferase; polymerase chain reaction; postdoctoral investigator; therapy design /development; transfection /expression vector; western blottings

DESCRIPTION (provided by applicant): Approximately 98 percent of cases of acute promyelocytic leukemia (APL) are associated with a specific t(15;17) chromosomal translocation that fuses the Retinoic Acid Receptor alpha (RARa) gene locus to the Promyelocytic Leukemia (PML) gene locus. The resulting PML-RARa fusion protein is necessary for leukemogenesis and confers retinoic acid responsiveness to leukemic cells. Treatment with retinoic acid results in differentiation of leukemic cells and clinical remission in APL patients. However, 15-20 percent of patients relapse, often necessitating autologous bone marrow transplantation that may further contribute to relapse due the presence of leukemic cells in the transplant. We propose to develop gene therapy for APL by combining lentiviral vector systems with the method of gene silencing by RNA interference (RNAi). The specific aims are: (1) Development of a lentiviral vector that delivers RNAi to downregulate expression of the PML-RARa fusion protein; and (2) Evaluation of lentiviral vector-mediated RNAi against PML-RARa in a mouse model of APL. Leukemic bone marrow cells will be transduced with lentiviral vectors prior to transplantation. Recipient mice will be monitored for disease to assess efficiency of PML-RARa silencing.

描述（由申请人提供）：大约 98% 的急性早幼粒细胞白血病 (APL) 病例与特定的 t(15;17) 染色体易位有关，该易位将视黄酸受体 α (RARa) 基因位点与早幼粒细胞白血病 (PML) 融合) 基因位点。由此产生的 PML-RARa 融合蛋白对于白血病发生是必需的，并赋予白血病细胞视黄酸反应性。视黄酸治疗可导致 APL 患者的白血病细胞分化和临床缓解。然而，15-20% 的患者会复发，通常需要自体骨髓移植，由于移植物中存在白血病细胞，这可能会进一步导致复发。我们建议通过将慢病毒载体系统与RNA干扰（RNAi）基因沉默方法相结合来开发APL的基因治疗。具体目标是：（1）开发慢病毒载体，通过RNAi下调PML-RARa融合蛋白的表达； (2)在APL小鼠模型中评估慢病毒载体介导的针对PML-RARa的RNAi。白血病骨髓细胞在移植前将用慢病毒载体转导。将监测受体小鼠的疾病情况，以评估 PML-RARa 沉默的效率。