PATHOBIOLOGY & GENE TRANSFER IN CARDIOVASCULAR DISEASE

病理学

• 批准号: 8172640
• 负责人: LAWRENCE CHAN
• 金额: $ 11.09万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172640
• 关键词: Amino Acids; Candidate Disease Gene; Cardiovascular Diseases; Catheters; Cholesterol; Computer Retrieval of Information on Scientific Projects Database; Defect; Development; Disease; Drainage procedure; Enzymes; Exons; Familial Hypercholesterolemia; Funding; Gene Transfer; Generations; Genes; Goals; Grant; Hepatic; Hepatic artery; Hepatocyte; Human; Inferior vena cava structure; Injection of therapeutic agent; Institution; Liver; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Macaca mulatta; Methods; Modeling; Monkeys; Nonsense Mutation; Phenotype; Plasma; Positioning Attribute; Production; Proteins; Receptor Gene; Research; Research Personnel; Resources; Safety; Source; Transgenes; United States National Institutes of Health; Venous; arterial lesion; gene therapy; helper-dependent adenoviral vector; hypercholesterolemia; intrahepatic; nonhuman primate; pressure; programs

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Familial hypercholesterolemia (FH) is a heritable disease that is believed to be an excellent candidate for gene therapy. SFBR maintains a unique colony of rhesus monkeys (Macacca mulatta) that carry a defective gene for the low density lipoprotein (LDL) receptor and provide a naturally occurring model of human familial hypercholesterolemia. The defect in LDL receptor of these monkeys has been identified as a nonsense mutation in exon 6 that results in the production of a protein truncated at a position corresponding to amino acid 284 of the human LDL receptor. This defect has segregated with the phenotype of spontaneous hypercholesterolemia through four generations. This is the only nonhuman primate model for FH and proof of efficacy and safety of gene therapy in this model would be a major accomplishment toward human gene therapy for this disease. The objective of the program project is to examine the effect of the hepatic transfer of rhesus and human LDL receptor genes to LDL receptor defective rhesus monkeys. The goal is to demonstrate that transgenes increase hepatic expression of LDL receptor, reduce plasma LDL levels, slow development of arterial lesions and are safe during a 24-month period. Three methods were used for hepatic delivery of helper-dependent adenoviral vector with LDL-R (HDAd-LDLR). First, a single injection of 5 x 10E12 vp/kg HDAd-LDLR was given intravenously (IV). The treatment lowered the plasma cholesterol level from 578 mg/dl to 276 mg/dl at 21 days after injection; however, cholesterol returned to the pretreatment level by 42 days. Treatment was associated with elevated liver enzymes. Second, the efficiency of hepatocyte transduction was increased by a direct HDAd injection into the hepatic artery while transiently raising intrahepatic pressure by a balloon catheter inserted in the inferior vena cava (IVC), blocking hepatic venous drainage, which was released immediately before HDAd injection.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 家族性高胆固醇血症（FH）是一种可遗传的疾病，被认为是基因疗法的极好候选者。 SFBR保持独特的恒河猴（Macacca Mulatta）菌落，该菌落具有低密度脂蛋白（LDL）受体的缺陷基因，并提供了人类家族性高胆固醇血症的天然模型。 这些猴子的LDL受体缺陷已被鉴定为外显子6中的废话突变，该突变导致在与人LDL受体的氨基酸284相对应的位置截断的蛋白质产生。 这种缺陷已通过四代自发性高胆固醇血症的表型隔离。 这是FH的唯一非人类灵长类动物模型，在该模型中，基因治疗的功效和安全性证明将是对这种疾病的人类基因疗法的重大成就。 该计划项目的目的是检查恒河猴和人LDL受体基因对LDL受体缺陷恒河猴的肝转移的影响。 目的是证明转基因会增加LDL受体的肝表达，降低血浆LDL水平，缓慢的动脉病变发展，并在24个月内安全。 使用三种方法用于用LDL-R（HDAD-LDLR）肝依赖性腺病毒载体的肝输送。 首先，静脉注射5 x 10E12 VP/kg HDAD-LDLR（IV）。注射后21天，该治疗将血浆胆固醇水平从578 mg/dL降低至276 mg/dl；但是，胆固醇在42天之前恢复到预处理水平。治疗与肝酶升高有关。 其次，通过直接将HDAD注射到肝动脉中，同时通过插入下腔静脉CAVA（IVC）插入的气球导管暂时升高肝内压力，从而提高了肝细胞转导的效率，从而阻止了肝静脉引流，并在HDAD注射之前释放出来。