title: Adeno-associated virus mediates long-term gene transfer and delivery of chondroprotective IL-4 to murine synovium.
abstract: Treatments for rheumatoid arthritis and other inflammatory arthropathies are often ineffective at preventing joint destruction. Long-term genetic modification of the cells lining the joint space (synoviocytes) in vivo represents a potential method for the treatment of these chronic conditions. However, a vector capable of efficiently transducing synoviocytes in vivo for a persistent period has not been available. The present report describes the genetic modification of synoviocytes in vivo using recombinant adeno-associated virus. High-titer adeno-associated virus encoding the gene for Escherichia coli beta-galactosidase was injected into the knee joints of mice. Synovial tissues were then examined for beta-galactosidase transgene expression by in situ staining and by fluorometry. High-efficiency, persistent transgene expression was observed in the synovium with no evidence of vector-induced inflammation. Expression was observed for at least 7 months and was higher in arthritic than nonarthritic mice. Gene transfer of murine IL-4 to the joints of mice with collagen-induced arthritis led to detectable levels of IL-4 in the joint and protection from articular cartilage destruction. These data suggest that adeno-associated virus may be a useful vector for gene delivery to the synovium for the treatment of inflammatory arthropathies.
authors.affiliation: William S. Rowe Division of Rheumatology, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: S
authors.initials: S
authors.lastname: Watanabe
authors.forename: T
authors.initials: T
authors.lastname: Imagawa
authors.forename: G P
authors.initials: GP
authors.lastname: Boivin
authors.forename: G
authors.initials: G
authors.lastname: Gao
authors.forename: J M
authors.initials: JM
authors.lastname: Wilson
authors.forename: R
authors.initials: R
authors.lastname: Hirsch
mesh_terms: D000818:Animals; D001168:Arthritis / Q000628:therapy; D002358:Cartilage, Articular / Q000473:pathology; D019902:Chondrocytes / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D004926:Escherichia coli / Q000201:enzymology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D015847:Interleukin-4 / Q000235:genetics* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010329:Patella / Q000378:metabolism; D011509:Proteoglycans / Q000096:biosynthesis; D013050:Spectrometry, Fluorescence; D013583:Synovial Membrane / Q000378:metabolism*; D013997:Time Factors; D019076:Transgenes; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D011509:Proteoglycans; D015847:Interleukin-4; D001616:beta-Galactosidase