title: Apolipoprotein A-V gene therapy for disease prevention / treatment: a critical analysis.
abstract: 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 lipase-mediated TG hydrolysis, another portion is recovered intracellularly, in association with cytosolic lipid droplets. Loss of apoA-V function is positively correlated with elevated plasma TG and increased risk of cardiovascular disease. Single nucleotide polymorphisms (SNP) in theAPOA5locus can affect transcription efficiency or introduce deleterious amino acid substitutions. Likewise, rare mutations inAPOA5that 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 deleteriousAPOA5SNPs 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 anAPOA5mutation/polymorphism and not have deleterious mutations/polymorphisms in other genes known to influence plasma TG levels.
authors.affiliation: Center for Prevention of Obesity, Diabetes and Cardiovascular Disease, Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
authors.forename: Trudy M
authors.initials: TM
authors.lastname: Forte
authors.affiliation: Center for Prevention of Obesity, Diabetes and Cardiovascular Disease, Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
authors.forename: Vineeta
authors.initials: V
authors.lastname: Sharma
authors.affiliation: Center for Prevention of Obesity, Diabetes and Cardiovascular Disease, Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA; rryan@chori.org.
authors.forename: Robert O
authors.initials: RO
authors.lastname: Ryan
keywords: adeno-associated virus; apolipoprotein A-V; atherosclerosis; gene therapy; lipoprotein lipase; single nucleotide polymorphism; triacylglycerol