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 (125)I-labeled LDL ((123)I-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 (123)I-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 (123)I-LDL injection and a progressive labeling of the bladder, starting 20 min after injection.

Low-density lipoprotein (LDL) receptor/transferrin fusion protein: in vivoproduction and functional evaluation as a potential therapeutic tool forlowering plasma LDL cholesterol / Razzini, Giorgia; Parise, Flavia; Calebiro, D; Battini, Renata; Bagni, Bruno; Corazzari, Tolmino; Tarugi, Patrizia Maria; Angelelli, Cecilia; Molinari, Susanna; Falqui, L; Ferrari, Stefano. - In: HUMAN GENE THERAPY. - ISSN 1043-0342. - STAMPA. - 15 (6):(2004), pp. 533-541. [10.1089/104303404323141980]

Low-density lipoprotein (LDL) receptor/transferrin fusion protein: in vivoproduction and functional evaluation as a potential therapeutic tool forlowering plasma LDL cholesterol.

RAZZINI, Giorgia;PARISE, Flavia;BATTINI, Renata;BAGNI, Bruno;CORAZZARI, Tolmino;TARUGI, Patrizia Maria;ANGELELLI, Cecilia;MOLINARI, Susanna;FERRARI, Stefano
2004

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 (125)I-labeled LDL ((123)I-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 (123)I-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 (123)I-LDL injection and a progressive labeling of the bladder, starting 20 min after injection.
15 (6)
533
541
Low-density lipoprotein (LDL) receptor/transferrin fusion protein: in vivoproduction and functional evaluation as a potential therapeutic tool forlowering plasma LDL cholesterol / Razzini, Giorgia; Parise, Flavia; Calebiro, D; Battini, Renata; Bagni, Bruno; Corazzari, Tolmino; Tarugi, Patrizia Maria; Angelelli, Cecilia; Molinari, Susanna; Falqui, L; Ferrari, Stefano. - In: HUMAN GENE THERAPY. - ISSN 1043-0342. - STAMPA. - 15 (6):(2004), pp. 533-541. [10.1089/104303404323141980]
Razzini, Giorgia; Parise, Flavia; Calebiro, D; Battini, Renata; Bagni, Bruno; Corazzari, Tolmino; Tarugi, Patrizia Maria; Angelelli, Cecilia; Molinari, Susanna; Falqui, L; Ferrari, Stefano
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/723243
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