Reconstitution of apo B mRNA Editing in Liver by Gene-Transfer as a Potential Approach for the Treatment of Severe Forms of Polygenic Hypercholesterolemia: An Outline of the Rationale

Abstract

SummaryApolipoprotein (apo) B is the essential structural protein of the atherogenic lipoproteins, most notably low density lipoproteins (LDL) and lipoprotein (Lp) a. The apo B mRNA is subject to a unique mRNA modification which is termed RNA editing: at nucleotide position 6666 the genomically encoded cytidine is post-transcriptionally deaminated to uridine. This renders amino acid residue 2351 from glutamin CAA into a translational stop codon UAA and therefore leads to the synthesis of the truncated isoform apo B48. Apo B mRNA editing with production of apo B48 has been previously thought to be limited to the small intestine. However, recent results have suggested that in contrast to man in many species apo B mRNA editing is not intestine specific but does occur also in liver. Since apo B48 apparently has an accelerated plasma turnover, apo B mRNA editing in liver limits the plasma concentration of the atherogenic LDL and Lpa. It is therefore proposed that the reconstitution of apo B mRNA editing in liver by gene transfer of the apo B mRNA editing enzyme is an attractive approach for lowering high plasma cholesterol. Current work in our laboratory is addressing the feasability, efficiency and physiological impact of hepatic gene transfer of the apo B mRNA editing enzyme. In the following article the background and rationale for this approach are outlined in detail.