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Helper-dependent adenovirus-mediated gene transfer of a secreted LDL receptor/transferrin chimeric protein reduces aortic atherosclerosis in LDL receptor-deficient mice

Gene Therapy (2019) | Download Citation


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 × 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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The authors wish to acknowledge the memory of Prof. Stefano Ferrari, who has started this project.

Author information


  1. CEINGE-Biotecnologie Avanzate, Napoli, Italy

    • Eleonora Leggiero
    • , Laura Iaffaldano
    • , Barbara Lombardo
    • , Adelaide Greco
    • , Matteo Gramanzini
    • , Donatella Montanaro
    • , Alfonso Baldi
    • , Vincenzo Cerullo
    • , Lucia Sacchetti
    •  & Lucio Pastore
  2. IRCCS SDN, Napoli, Italy

    • Giuseppe Labruna
    •  & Dario Fiorenza
  3. Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Napoli, Italy

    • Laura Iaffaldano
    • , Barbara Lombardo
    • , Vincenzo Cerullo
    •  & Lucio Pastore
  4. Dipartimento di Scienze Biomediche Avanzate, Università degli Studi di Napoli Federico II, Napoli, Italy

    • Adelaide Greco
  5. Istituto di Biostrutture e Bioimmagini, CNR, Napoli, Italy

    • Adelaide Greco
    •  & Matteo Gramanzini
  6. Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, Caserta, Italy

    • Alfonso Baldi
  7. Laboratory of ImmunoViroTherapy, Centre for Drug Research (CDR), Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland

    • Vincenzo Cerullo


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The authors declare that they have no conflict of interest.

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Correspondence to Lucio Pastore.

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