Gene Transfer of Cytidine Deaminase apoBEC-1 Lowers Lipoprotein(a) in Transgenic Mice and Induces Apolipoprotein B Editing in Rabbits

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Abstract
Apolipoprotein (apo) B100 is an essential component of low-density lipoproteins (LDL) and lipoprotein(a) [Lp(a)]. In mammals, apoB can be edited post-transcriptionally to encode a truncated form of apoB (apoB48) that is unable to form either of these atherogenic lipoproteins. To study the effect of increasing hepatic apoB editing activity on formation of Lp(a), a recombinant adenovirus encoding rat apoBEC-1, the cytidine deaminase component of the apoB mRNA editing complex, was administered to human apoB/apo(a) transgenic mice. This resulted in expression of apoBEC-1 in hepatocytes of these mice, increased hepatic editing of human apoB mRNA, and decreased plasma levels of human apoB100 and Lp(a). The apoBEC-1 recombinant adenovirus was also administered to rabbits, an animal which, like humans, naturally lacks hepatic apoB editing. Expression of the exogenous apoBEC-1 in rabbit liver resulted in editing of up to 10% of apoB mRNA. Hepatic apoB editing was associated with lower LDL levels in these rabbits relative to those treated with a control adenovirus. However, LDL levels were elevated significantly in both animals as a result of adenovirus injection. These studies demonstrate that introduction of the cytidine deaminase apoBEC-1 is sufficient to induce hepatic apoB editing in an animal lacking this activity, and that induction of editing could serve as a novel approach for lowering plasma concentrations of the atherogenic lipoproteins Lp(a) and LDL. The aim of this study was to evaluate the feasibility and potential of inducing apoB mRNA editing for reducing atherosclerosis risk. Results indicate that transfer of a single gene, apoBEC-1, can increase hepatic apoB mRNA editing in human apoB/apo(a) transgenic mice, causing a significant reduction in plasma levels of the atherogenic lipoprotein Lp(a). Induction of hepatic apoB editing in an animal normally lacking this activity (the rabbit) provides additional evidence that apoBEC-1 gene transfer would be effective in humans. ApoB editing in rabbit liver was associated with reduced LDL levels, although nonspecific effects of adenovirus on LDL offset any therapeutic potential for lowering atherosclerosis risk using this strategy. Although the current study identifies a useful route to reduce LDL and Lp(a) levels, it also underscores the need to develop more stable gene transfer vectors that lack pathologic effects on the target organ.