Organ distribution of gene expression after intravenous infusion of targeted and untargeted lentiviral vectors

• Published in: Gene therapy Vol. 8; no. 19; pp. 1456 - 1463
• Main Authors: PENG, K-W, PHAM, L, YE, H, ZUFFEREY, R, TRONO, D, COSSET, F-L, RUSSELL, S. J
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01-10-2001
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Applied cell therapy and gene therapy; Biological and medical sciences; Biotechnology; Bone marrow; Cardiac muscle; Cell cycle; Epidermal Growth Factor - genetics; Epidermal Growth Factor - metabolism; epidermal growth factor receptors; Expression vectors; Female; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene Targeting; Gene therapy; Gene transfer; Genetic Vectors - genetics; Glycoproteins; Health. Pharmaceutical industry; HIV; HIV-1 - genetics; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Industrial applications and implications. Economical aspects; Intravenous administration; Kidneys; Lentivirus; Leukemia Virus, Murine - genetics; Liver; Liver - metabolism; luciferase gene; Luciferases - genetics; Medical sciences; Mice; Mice, Inbred BALB C; Murine leukemia virus; Myocardium - metabolism; Polymerase Chain Reaction; Proteinase; Receptor, Epidermal Growth Factor - metabolism; Recombinant Proteins - metabolism; Skeletal muscle; Spleen; Spleen - metabolism; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Targeting; Recombinant virus; Rodentia; Glycoprotein; Retroviridae; Lentivirus; Virus; Mammalian type C retrovirus; Vertebrata; Membrane receptor; Mammalia; Epidermal growth factor; Mouse; Distribution; Murine leukemia virus; Gene therapy; Virus envelope; Vector
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/sj.gt.3301552

Lentiviral vectors represent an attractive technology platform from which to develop a targetable injectable gene delivery system for transduction of specific cell populations in vivo, irrespective of their cell cycle status. Targeted HIV-1-based lentiviral vectors were generated by pseudotyping them with chimeric murine leukemia virus (MLV) envelope glycoproteins displaying N-terminal targeting polypeptides. Vectors displaying an EGF polypeptide were fully infectious on EGF receptor-negative cells, but were inactive on cells with abundant EGF receptors (inverse targeting). Receptor-mediated inactivation of gene transfer was overcome by competing the EGF receptors on the target cells with soluble EGF or by removing the displayed EGF domain from the surface of the vector particles by factor Xa cleavage of a specific protease substrate engineered into its tethering linker (protease targeting). Intravenous infusion of nontargeted HIV-1 vectors led to maximal luciferase activity in liver and spleen with moderate or minimal activity in heart, skeletal muscle, lung, brain, kidney, ovaries and bone marrow. In contrast, intravenous EGF-displaying vectors were expressed maximally in spleen with very low level luciferase expression detectable in liver (EGF-receptor rich). Liver transduction by the EGF-displaying vector was restored by pretreating the animals with soluble EGF suggesting that these vectors are inversely targeted to spleen.