Low-Density Lipoprotein (LDL) Receptor/Transferrin Fusion Protein:In VivoProduction and Functional Evaluation as a Potential Therapeutic Tool for Lowering Plasma LDL Cholesterol

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Abstract
A soluble form of human low-density lipoprotein receptor (LDL-R) fused in frame with rabbit transferrin (LDL-Rs(hu)/Tf-rab) is assessed in vivo as a therapeutic tool for lowering plasma LDL cholesterol. The cDNA encoding LDL-Rs(hu)/Tf-rab is expressed in mice, using a hydrodynamics-based gene transfer procedure. The transgene is transcribed in the liver of transduced animals and the corresponding protein is secreted into the bloodstream. Circulating LDL-Rs(hu)/Tf-rab binds LDL specifically, thus indicating that it is correctly processed through the cellular compartments in vivo. More importantly, the expression of LDL-Rs(hu)/Tf-rab allows the removal of injected human I-125-labeled LDL (I-123-LDL) from the bloodstream of transduced CD1 mice, which show faster LDL plasma clearance, anticipating by approximately 90 min the same clearance value observed in control animals. A similar effect is observed in transduced LDL-R-/- mice, in which the clearance of injected human LDL depends solely on the presence of circulating LDL-Rs(hu)/Tf-rab. In these animals the extent of plasma LDL clearance is directly related to the concentration of LDL-Rs(hu)/Tf-rab in the blood. Finally, LDL-Rs(hu)/Tf-rab does not alter the pattern of LDL organ distribution: in transduced animals, as well as in control animals, liver and bladder are the predominantly labeled organs after I-123-LDL injection. However, LDL-Rs(hu)/Tf-rab has a quantitative effect on LDL tissue deposition: in treated animals LDL-Rs(hu)/Tf-rab determines an increase in radioactivity in the liver at early times after I-123-LDL injection and a progressive labeling of the bladder, starting 20 min after injection