PATHOBIOLOGY & GENE TRANSFER IN CARDIOVASCULAR DISEASE

病理学

• 批准号: 7957881
• 负责人: LAWRENCE CHAN
• 金额: $ 7.26万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-06 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7957881
• 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; Primates; 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.

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