Assessment of HD-AD vectors and factor IX and APOA-1

HD-AD 载体以及因子 IX 和 APOA-1 的评估

• 批准号: 6719187
• 负责人: ARTHUR L. BEAUDET
• 金额: $ 25.99万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6719187
• 关键词: Adenoviridae; apolipoproteins; atherosclerosis; baboons; biotechnology; coagulation factor IX; experimental designs; gene delivery system; gene therapy; helper virus; laboratory mouse; low density lipoprotein receptor; nonhuman therapy evaluation; technology /technique development; therapy adverse effect; thrombocytopenia; transfection /expression vector

The overall goals of this project are to further define the safety and toxicity of helper-dependent adenoviral (HD-Ad) vectors, to delineate the pathogenesis of the thrombocytopenia observed with the HD-Ad vectors, to attempt to identify mechanisms to circumvent the thrombocytopenia, to develop experience with these vectors in primates, and to move incrementally towards clinical trials with these very promising HD-Ad vectors. The pathogenesis of the thrombocytopenia will be studied in mice, focusing on direct interactions between platelets and vector and between endothelial cells and vector. One very important aim will be to evaluate safety, toxicity, and short-term expression using high doses of HD-Ad vectors in juvenile baboons. Because of the desire to initiate clinical trials with maximum safety, we are comparing the expression of factor IX and apolipoprotein A-I (apo A-I) with IM administration utilizing a muscle-specific promoter and IV administration aimed at expression in hepatocytes. Another aim will be to put in place all of the necessary reagents and commitments to prepare GMP quality HD-Ad vector suitable for use in pre-clinical and clinical studies. Toxicity studies with GMP quality vector will be conducted in mice and baboons. In longer-term experiments in baboons, we will test whether over-expression of apo A-I will protect against atherosclerosis in baboons. Finally, we propose to develop a clinical trial to introduce the HD-Ad vectors into the clinic using either IM or IV administration. No IRB-approved protocol is available at present, but the major possibilities under consideration include expression of factor IX in patients with hemophilia B or expression of apo A-I in patients with coronary artery disease and low production of apo A-I. The long-term significance of this project is to attempt to develop HD-Ad vectors designed to increase expression of the LDL receptor and/or apo A-I in humans. If successful, this approach could have a major impact on prevention or reduction of atherosclerosis in the human population.

The overall goals of this project are to further define the safety and toxicity of helper-dependent adenoviral (HD-Ad) vectors, to delineate the pathogenesis of the thrombocytopenia observed with the HD-Ad vectors, to attempt to identify mechanisms to circumvent the thrombocytopenia, to develop experience with these vectors in primates, and to move incrementally towards clinical trials with these very promising高清媒介。血小板减少症的发病机理将在小鼠中研究，重点是血小板与载体之间的直接相互作用以及内皮细胞与载体之间的直接相互作用。一个非常重要的目的是使用高剂量的HD-AD载体在少年狒狒中评估安全性，毒性和短期表达。由于希望以最高安全性启动临床试验，我们正在比较 IM IX和载脂蛋白A-I（Apo A-I）具有IM给药，利用肌肉特异性启动子和旨在在肝细胞中表达的IV给药。另一个目的是制定所有必要的试剂和承诺，以准备适合于临床前和临床研究使用的GMP质量HD-AD载体。使用GMP质量载体的毒性研究将在小鼠和狒狒中进行。在狒狒的长期实验中，我们将测试Apo A-I的过度表达是否会预防狒狒的动脉粥样硬化。最后，我们建议开发一项临床试验，使用IM或IV给药将HD-AD向量引入诊所。目前尚无IRB批准的协议，但主要可能性 正在考虑的因素包括血友病患者中IX因子的表达或冠状动脉疾病患者的APO A-I表达和APO A-I产生较低的患者。该项目的长期意义是试图开发旨在增加人类中LDL受体和/或APO A-I表达的HD-AD载体。如果成功的话，这种方法可能会对预防或减少人口动脉粥样硬化产生重大影响。