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 × 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_name
Gene Therjournal_title
Gene therapyauthors
Watson RS,Broome TA,Levings PP,Rice BL,Kay JD,Smith AD,Gouze E,Gouze JN,Dacanay EA,Hauswirth WW,Nickerson DM,Dark MJ,Colahan PT,Ghivizzani SCdoi
10.1038/gt.2012.81subject
Has Abstractpub_date
2013-06-01 00:00:00pages
670-7issue
6eissn
0969-7128issn
1476-5462pii
gt201281journal_volume
20pub_type
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