Insulin-like growth factor-I gene therapy for articular cartilage repair
The aim of this thesis was to explore the possibility of using insulin-like growth factor-I gene therapy to upregulate IGF-I production in synovium and transplanted chondrocytes to achieve enhanced articular cartilage repair in the horse. The specific aims of the research were to inject an adenoviral IGF-I vector construct directly into the joint to transduce synovial membrane and increase IGF-I concentration in synovial fluid; transduce chondrocytes ex vivo and subsequently transplant them into large osteochondral defects to enhance cartilage healing and; extend transplant chondrocyte survival by ex vivo transduction with AdIGF-I.
AdIGF-I was injected into fetlock joints of horses at increasing doses of viral particles. The highest dose of viral particles injected (50 billion) significantly increased IGF-I concentrations in synovial fluid for a period of approximately 3 to 21 days with levels returning to or near, baseline values by Day 28. Transcription of IGF-I in the synovium also increased with increasing viral particles, however, an increased polymorphonuclear cell infiltrate occurred in the synovial tissue. Elevated levels of IGF-I concentrations were achieved with direct injection of AdIGF-I with a mild amount of undesirable inflammatory cell infiltrate.
Chondrocytes were transduced with AdIGF-I ex vivo and implanted into large osteochondral defects made on the lateral troclear ridge of the femoropatellar joints of horses. The genetically modified repair tissue was compared to the repair tissue of naïve chondrocytes. AdIGF-I genetic modification enhanced many aspects of cartilage healing especially at 4 and 9 weeks post transplantation. At 8 months, healing of the treated and control defects were similar.
AdIGF-I genetic modification of chondrocytes increased the longevity of the transplanted chondrocytes. IGF-I genetically modified chondrocytes could be detected at 4 weeks and 8 months. Naïve transplanted chondrocytes were detectable in only one horse at 4 weeks and undetectable at 8 months indicating that AdIGF-I modification may enhance cell survival. The extended survival of the genetically modified chondrocytes may accelerate cartilage repair in large osteochondral defects of horses especially in the short-term stages of healing.
0541: Biomedical research