title: In vivo gene delivery to synovium by lentiviral vectors.
abstract: The delivery of anti-arthritic genes to the synovial lining of joints is being explored as a strategy for the treatment of rheumatoid arthritis. In this study, we have investigated the use of VSV-G pseudotyped, HIV-1-based lentiviral vectors for gene delivery to articular tissues. Recombinant lentivirus containing a beta-galactosidase/neomycin resistance fusion gene under control of the elongation factor (EF) 1alpha promoter efficiently transduced human and rat synoviocytes and chondrocytes in cell culture. When directly injected into the knees of rats, this vector transduced synovial lining cells, but not other articular tissues such as cartilage. We also constructed a lentiviral vector containing the human interleukin-1 receptor antagonist (IL1RA) cDNA and examined transgene expression in vitro and in vivo following injection into the knee joints of rats. In immunocompetent animals, intra-articular IL1RA expression was high and persisted, at a sharply declining rate, for approximately 20 days. In immunocompromised rats, however, lentivirus-mediated intra-articular expression of human IL1RA was found to persist for at least 6 weeks. Extra-articular expression of the transgene was minimal. These results indicate that lentiviral vectors are capable of efficient in vivo gene transfer to synovium and merit further investigation as a means of providing long-term expression for gene-based treatments of arthritis.
authors.affiliation: Center for Molecular Orthopaedics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Elvire
authors.initials: E
authors.lastname: Gouze
authors.forename: Robert
authors.initials: R
authors.lastname: Pawliuk
authors.forename: Carmencita
authors.initials: C
authors.lastname: Pilapil
authors.forename: Jean-Noel
authors.initials: JN
authors.lastname: Gouze
authors.forename: Christina
authors.initials: C
authors.lastname: Fleet
authors.forename: Glyn D
authors.initials: GD
authors.lastname: Palmer
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Evans
authors.forename: Philippe
authors.initials: P
authors.lastname: Leboulch
authors.forename: Steven C
authors.initials: SC
authors.lastname: Ghivizzani
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D001172:Arthritis, Rheumatoid / Q000628:therapy; D004351:Drug Resistance / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D008297:Male; D009355:Neomycin / Q000494:pharmacology; D009928:Organ Specificity; D051381:Rats; D011923:Rats, Nude; D017208:Rats, Wistar; D012795:Sialoglycoproteins / Q000235:genetics / Q000493:pharmacokinetics; D013583:Synovial Membrane / Q000378:metabolism*; D001616:beta-Galactosidase / Q000235:genetics
chemical_list: D018501:Antirheumatic Agents; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D012795:Sialoglycoproteins; D001616:beta-Galactosidase; D009355:Neomycin