Gene therapy for acute promyelocytic leukemia

急性早幼粒细胞白血病的基因治疗

• 批准号: 7270470
• 负责人: SIMONE V WARD
• 金额: $ 5.2万
• 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 2008-08-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7270470
• 关键词: A Mouse; Acute Myelocytic Leukemia; Acute Promyelocytic Leukemia; Autologous Bone Marrow Transplantation; Biological Models; Bone Marrow; Bone Marrow Cells; Cells; Chimeric Proteins; Chromosomal translocation; Clinical; DNA Repair Enzymes; Development; Differentiation Therapy; Disease; Disease remission; Evaluation; Exclusion; Fellowship; Fluorescence-Activated Cell Sorting; Fusion Protein Expression; Gene Silencing; Generations; Genes; Goals; Green Fluorescent Proteins; Hematopoietic stem cells; Individual; Kinetics; Lentivirus Vector; Leukemic Cell; Mediating; Methods; Monitor; Mus; Names; Northern Blotting; O(6)-Methylguanine-DNA Methyltransferase; Oncogene Activation; Oncogenic; Patients; Proteins; RARA gene; RNA Interference; Relapse; Reverse Transcriptase Polymerase Chain Reaction; Risk; Small Interfering RNA; Subfamily lentivirinae; System; Testing; Time; Transplantation; Tretinoin; Trypan Blue; Western Blotting; Work; cellular transduction; gene therapy; in vivo; leukemia; leukemogenesis; mouse model; mutant; promoter; research study; retinoic acid receptor alpha; therapeutic gene; vector; vector control; ward

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％的急性前临床细胞性白血病病例（APL）与特定的T（15; 17）染色体易位有关，该染色体易位融合了视黄酸酸受体α（RARA）基因座与前叶状细胞性白血病（PML）基因locus。产生的PML-RARA融合蛋白对于白血病发生是必要的，并赋予视黄酸对白血病细胞的反应。维甲酸治疗导致白血病细胞和APL患者的临床缓解分化。然而，15-20％的患者复发，通常需要自体骨髓移植，这可能会进一步导致复发，这是由于移植中存在白血病细胞。我们建议通过将慢病毒载体系统与RNA干扰（RNAI）结合基因沉默的方法来开发APL的基因疗法。具体目的是：（1）发育的慢病毒载体，该向肠内载体下调PML-RARA融合蛋白的表达； （2）在APL的小鼠模型中评估慢病毒载体介导的RNAi针对PML-RARA。在移植之前，将用慢病毒载体转导白血病骨髓细胞。将监测受体小鼠的疾病，以评估PML-RARA沉默的效率。