scAAV-mediated gene transfer of interleukin-1-receptor antagonist to synovium and articular cartilage in large mammalian joints

    Authors

    R. S. Watson; T. A. Broome; P. P. Levings; B. L. Rice; J. D. Kay; A. D. Smith; E. Gouze; J. N. Gouze; E. A. Dacanay; W. W. Hauswirth; D. M. Nickerson; M. J. Dark; P. T. Colahan;S. C. Ghivizzani

    Comments

    Authors: contact us about adding a copy of your work at STARS@ucf.edu

    Abbreviated Journal Title

    Gene Ther.

    Keywords

    osteoarthritis; self-complementary adeno-associated virus; interleukin-1-receptor antagonist; synovium; cartilage; equine; ADENOASSOCIATED VIRUS AAV; LAMININ RECEPTOR; IN-VIVO; ARTHRITIS; VECTORS; DELIVERY; THERAPY; TRANSDUCTION; EXPRESSION; OSTEOARTHRITIS; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental

    Abstract

    With the long-term goal of developing a gene-based treatment for osteoarthritis (OA), we performed studies to evaluate the equine joint as a model for adeno-associated virus (AAV)-mediated gene transfer to large, weight-bearing human joints. A self-complementary AAV2 vector containing the coding regions for human interleukin-1-receptor antagonist (hIL-1Ra) or green fluorescent protein was packaged in AAV capsid serotypes 1, 2, 5, 8 and 9. Following infection of human and equine synovial fibroblasts in culture, we found that both were only receptive to transduction with AAV1, 2 and 5. For these serotypes, however, transgene expression from the equine cells was consistently at least 10-fold higher. Analyses of AAV surface receptor molecules and intracellular trafficking of vector genomes implicate enhanced viral uptake by the equine cells. Following delivery of 1 x 10(11) vector genomes of serotypes 2, 5 and 8 into the forelimb joints of the horse, all three enabled hIL-1Ra expression at biologically relevant levels and effectively transduced the same cell types, primarily synovial fibroblasts and, to a lesser degree, chondrocytes in articular cartilage. These results provide optimism that AAV vectors can be effectively adapted for gene delivery to large human joints affected by OA.

    Journal Title

    Gene Therapy

    Volume

    20

    Issue/Number

    6

    Publication Date

    1-1-2013

    Document Type

    Article

    Language

    English

    First Page

    670

    Last Page

    677

    WOS Identifier

    WOS:000319976600010

    ISSN

    0969-7128

    Share

    COinS