Helper-dependent adenovirus-mediated gene transfer of a secreted LDL receptor/transferrin chimeric protein reduces aortic atherosclerosis in LDL receptor-deficient mice
Helper-dependent adenovirus-mediated gene transfer of a secreted LDL receptor/transferrin chimeric protein reduces aortic atherosclerosis in LDL receptor-deficient mice(69 visite)(PDF pubblico24 visite) Leggiero E, Labruna G, Iaffaldano L, Lombardo B, Greco A, Fiorenza D, Gramanzini M, Montanaro D, Baldi A, Cerullo V, Sacchetti L, Pastore L
Gene Ther (ISSN: 0969-7128linking), 2019 Jan 30; 26(3-4): 121-130.
Tipo di articolo: Journal Article
Impact factor: 4.782, Impact factor a 5 anni: 3.67
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Affiliazioni:
*** IBB - CNR *** CEINGE-Biotecnologie Avanzate, Napoli, Italy., IRCCS SDN, Napoli, Italy., Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita degli Studi di Napoli Federico II, Napoli, Italy., Dipartimento di Scienze Biomediche Avanzate, Universita degli Studi di Napoli Federico II, Napoli, Italy., Istituto di Biostrutture e Bioimmagini, CNR, Napoli, Italy., Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy., Laboratory of ImmunoViroTherapy, Centre for Drug Research (CDR), Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland., CEINGE-Biotecnologie Avanzate, Napoli, Italy. lucio.pastore@unina.it., Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita degli Studi di Napoli Federico II, Napoli, Italy. lucio.pastore@unina.it.,
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Familial hypercholesterolemia (FH) is a genetic hyperlipidemia characterized by elevated concentrations of plasma LDL cholesterol. Statins are not always effective for the treatment of FH patients; unresponsive patients have poor prognosis and rely on LDL apheresis. In the past, we developed safe and effective gene therapy strategies for the expression of anti-atherogenic proteins using PEGylated helper-dependent adenoviral (HD-Ad) vectors. We recently developed a HD-Ad vector for the expression of the soluble form of the extracellular portion of the human LDL receptor (LDLR) fused with a rabbit transferrin dimer (LDLR-TF). We evaluated the efficacy of the LDLR-TF chimeric protein in CHOLDLA7, a cell line lacking LDLR expression, restoring the ability to uptake LDL. Subsequently, we administered intravenously 1 x 10E13 vp/kg of this vector in LDLR-deficient mice and observed amelioration of lipid profile and reduction of aortic atherosclerosis. Finally, we studied LDL distribution after HD-Ad vector-mediated expression of LDLR-TF in LDLR-deficient mice and found LDL accumulation in liver, and in heart and intestine. These results support the possibility of lowering LDL-C levels and reducing aortic atherosclerosis using a secreted therapeutic transgene; the present strategy potentially can be modified and adapted to non-systemic gene transfer with expression of the secreted chimeric protein in muscle or other tissues. Intramuscular or local administration strategies could improve the safety profile of this strategy and facilitate applicability.
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594 Records (543 escludendo Abstract e Conferenze). Impact factor totale: 2426.969 (2262.484 escludendo Abstract e Conferenze). Impact factor a 5 anni totale: 2471.461 (2296.44 escludendo Abstract e Conferenze).