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

A soluble form of human low-density lipoprotein receptor (LDL-R) fused in frame with rabbit transferrin (LDL-Rshu/Tfrab) is assessed in vivo as a therapeutic tool for lowering plasma LDL cholesterol. The cDNA encoding LDL-Rshu/Tfrab 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-Rshu/Tfrab binds LDL specifically, thus indicating that it is correctly processed through the cellular compartments in vivo. More importantly, the expression of LDL-Rshu/Tfrab allows the removal of injected human 125I-labeled LDL (123I-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 LD...