Potential role of direct adenoviral gene transfer in enhancing fracture repair.

Abstract

Gene therapy has much to offer in the treatment of conditions in which it is necessary to increase the formation of bone. Nonunions, segmental defects, and aseptic loosening are examples of conditions where the local expression of genes that inhibit osteolysis and promote osteogenesis might be helpful. Studies in which one such possibility has been evaluated experimentally are described. These investigations used a surgically produced segmental defect in the femurs of New Zealand White rabbits as the model system. Adjacent muscle was fashioned around the defect to form a chamber into which adenoviral vectors were injected. High levels of transgene expression were found in the muscle surrounding the defect after injection of vectors carrying marker genes. Transgene expression also was seen in the cut ends of the bone and the scar tissue within the gap. No transgene expression was seen in the contralateral limb, spleen, or lung; transient, low levels of expression were found in the liver. Transgene expression declined with time, disappearing from all tissue but bone by Day 26; expression persisted in bone for at least 6 weeks. The control defects did not heal spontaneously. Injection of adenovirus carrying a human bone morphogenetic protein-2 complementary deoxyribonucleic acid led to healing of the segmental defect within 12 weeks, as judged by radiographic, histologic, and biomechanical criteria. Adenovirus carrying a human transforming growth factor-beta 1 complementary deoxyribonucleic acid showed signs of improved healing, but not to the extent seen with the bone morphogenetic protein-2 complementary deoxyribonucleic acid. This approach to therapy holds much promise as a novel means of promoting osteogenesis.