Gene Therapy for Fracture Repair
Final rept. 15 Nov 2002-14 Apr 2007
LOMA LINDA VETERANS ASSOCIATION FOR RESEARCH AND EDUCATION CA
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These studies examined approaches to optimize gene therapy for the repair of endochondral bone fractures. Several components of a gene therapy approach were examined, including viral vectors and associated regulatory elements, vector delivery to the fracture tissues, and the application of a combination of genes with different functions in bone formation and tissue repair. It was found that the murine leukemia-based viral vector, with transgene expression mediated by the long terminal repeat, provided more robust, though unregulated, gene expression than the lentiviral vector transgenes expressed from either non-specific or bone-specific promoters. Viral vector delivery was important in promoting fracture healing, as demonstrated through an intramedullary technique for vector application. The application of a combination of fibroblast growth factor-2 and bone morphogenetic protein-4 transgenes, that mediate proliferation and osteogenesis, respectively, suggested that combination gene therapy could be an important clinical approach for bone healing. Microarray studies also characterized global gene expression during the early inflammation phase and the later endochondral bone formation phase of normal fracture healing fracture healing. Several thousand genes displayed expression changes during fracture healing, including genes that have been associated with tissue regeneration, and identified candidates for future fracture repair studies using optimized vectors and delivery techniques.
- Genetic Engineering and Molecular Biology
- Anatomy and Physiology
- Medicine and Medical Research