1998 Volvo Award winner in basic science studies - Lumbar spine fusion by local gene therapy with a cDNA encoding a novel osteoinductive protein (LMP-1)

Study Design. A posterior arthrodesis animal model using local expression of a newly discovered osteoin-ductive protein delivered in bone marrow cells. Objective. To introduce The concept of local gene therapy and determine its feasibility for achieving lumbar spine fusion using a gene for a novel osteoinductive protein: LIM Mineralization Protein-1 (LMP-1). Summary of Background Data. Extensive work is currently underway to improve the healing success and morbidity associated with the gold Standard bone-grafting material of autogenous iliac crest. As a result, alternative osteoinductive proteins and new-delivery methods warrant investigation. The authors' laboratory recently identified a novel gene that had osteoinductive capacity in vitro and is therefore a candidate for a new in vivo osteoinductive agent. Methods. Single-level posterior lumbar and thoracic arthrodesis was attempted in 14 athymic rats. The graft material, which consisted of a devitalized bone matrix (no osteoinductive activity) soaked with 0.75 to 1.5 million bone marrow cells, was inserted with the dorsal spine exposed. In each rat, one site received marrow cells transfected with the cDNA encoding a novel osteoinductive protein. At the other site for a control, the marrow cells were transfected with the reverse copy of the cDNA that did not express any protein. Transfection of marrow cells for 2 hours was accomplished using the mammalian expression vector pCMV2. Rats were killed after 4 weeks, and the spines were evaluated by manual palpation, radiographs, and nondecalcified histology. Results. In the pivotal experiment, successful spine fusion was obtained in 9/9 (100%) of the sites receiving marrow cells transfected with the active LMP-1 cDNA and in 0/9 (0%) of the sites receiving marrow cells transfected with the reverse (inactive) LMP-1 cDNA. Radiographs and histology confirmed the manual palpation results, demonstrating controlled new bone formation in the carrier and marrow transfected with the active LMP-1 cDNA and essentially no bone induction in the sites treated with marrow cells that did not express the protein. Conclusions. These data confirm that local delivery of the novel LMP-1 cDNA using bone marrow cells is feasible in vivo. Furthermore, these results demonstrate that posterior thoracic or lumbar spine fusion can be achieved in rats by local delivery of the LMP-1 cDNA.