Potential Role for Gene Therapy in the Enhancement of Fracture Healing

Various proteins have the potential to initiate and accelerate fracture healing. Although osteogenic growth factors are the most prominent of these, there also may be important roles for other agents including growth factor receptors, angiogenic factors, and cytokine antagonists. Gene based delivery systems offer the potential to achieve therapeutic levels of these proteins locally within the fracture site for sustained times. Moreover, these delivery systems may deliver their products in a more biologically active form than that achieved by the exogenous application of recombinant proteins. Genes may be transferred to fractures by direct in vivo delivery or by indirect ex vivo delivery, using viral or nonviral vectors. Two examples are described in this article. With an ex vivo procedure, it was possible to transfer lac Z and neo(r) marker genes to the bones of mice, using retroviral transduction of bone marrow stromal cells. Gene expression in vivo persisted for several weeks. This procedure has the advantage of providing not only gene products but also osteoprogenitor cells to sites of bone healing. In vivo, local transfer of the lucerifase and lac Z marker genes was accomplished in a segmental defect model in the rabbit using adenoviral vectors. Under these conditions, gene expression in most tissues in and around the defect lasted between 2 and 6 weeks. These data encourage additional development of gene therapy for fracture healing. Such developments should go hand in hand with studies in the basic biology of fracture healing.