Apolipoprotein A-V gene therapy for disease prevention/treatment:a critical analysis

查看全文 作　　者：Trudy [1]M.Forte;Vineeta [1]Sharma;Robert [1]O.Ryan 机构地区：[1]Center for Prevention of Obesity,Diabetes and Cardiovascular Disease,Children's Hospital Oakland Research Institute 出　　处：《The Journal of Biomedical Research》索引2016年第30卷第2期,共6页 基　　金：Supported by a grant from NIH(R37-HL64159);an AHA Postdoctoral Fellowship Award(VS) 摘　　要：Apolipoprotein(apo) A-V is a novel member of the class of exchangeable apo's involved in triacylglycerol(TG)homeostasis.Whereas a portion of hepatic-derived apoA-V is secreted into plasma and functions to facilitate lipoprotein Iipase-mediated TG hydrolysis,another portion is recovered intracellularly,in association with cytosolic lipid droplets.Loss of apo A-V function is positively correlated with elevated plasma TG and increased risk of cardiovascular disease.Single nucleotide polymorphisms(SNP) in the APOA5 locus can affect transcription efficiency or introduce deleterious amino acid substitutions.Likewise,rare mutations in APOA5 that compromise functionality are associated with increased plasma TG and premature myocardial infarction.Genetically engineered mouse models and human population studies suggest that,in certain instances,supplementation with wild type(WT) apoA-V may have therapeutic benefit.It is hypothesized that individuals that manifest elevated plasma TG owing to deleterious APOA5 SNPs or rare mutations would respond to WT apoA-V supplementation with improved plasma TG clearance.On the other hand,subjects with hypertriglyceridemia of independent origin(unrelated to apoA-V function) may not respond to apoA-V augmentation in this manner.Improvement in the ability to identify individuals predicted to benefit,advances in gene transfer technology and the strong connection between HTG and heart disease,point to apoA-V supplementation as a viable disease prevention / therapeutic strategy.Candidates would include individuals that manifest chronic TG elevation,have low plasma apoA-V due to an APOA5 mutation/polymorphism and not have deleterious mutations/polymorphisms in other genes known to influence plasma TG levels. 关 键 词：心血管疾病 基因治疗 载脂蛋白 疾病预防 单核苷酸多态性 批判性 甘油三酯 基因突变