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 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.

New insights into apolipoprotein A5 in controlling lipoprotein metabolism in obesity and the metabolic syndrome patients

“…Knockdown APOA5 gene in mice confers a four-fold increase of plasma TG levels, whereas high-expression of the human APOA5 gene in mice leads to a decrease of TG by approximately 50% [ 60 ]. Moreover, human genetic studies have identified several APOA5 SNPs affected plasma TG levels [ 61 ]. Inherited deficiency of the APOA5 gene in humans leaded to severe hypertriglyceridemia.…”

Non-Alcoholic Fatty Liver Disease and Cardiovascular Risk: Scientific Problem State

“…Несколько апо-липопротеинов, включая Апо А4, Апо А5, Апо С3 и Апо Е, могут влиять на липидный обмен при НАЖБП [29]. При этом полиморфизмы генов аполипопротеи-нов были обнаружены у пациентов с НАЖБП [30,31].…”

Recent Advances in the Genetics of Atherothrombotic Disease and Its Determinants

“…53 For instance, in 313 patients with FH who were evaluated using a targeted next-generation sequencing panel and an assay to detect large-scale copy-number variation, Wang et al 54 found a genetic basis for extremely elevated LDL-C in ≈67% of patients. Of these individuals, 45% had a monogenic largeeffect variant, 6% had a copy-number variation, and 17% had a strong polygenic component, as defined by accumulation of common GWAS-identified SNPs associated with LDL-C levels.…”