Gene therapy for spinal fusion.
ABSTRACT Spinal fusion will continue to be an important part of the surgical treatment of spinal pathology for the foreseeable future. Traditional challenges to successful spinal fusion surgery include autograft donor site morbidity and pseudoarthrosis. Recent advances in the understanding of the biology of bone formation have allowed the development of therapeutic biologics. Although recombinant bone morphogenetic proteins delivered to the arthrodesis site will stimulate fusion, these proteins have been less successful in more challenging fusion situations (posterolateral), require supraphysiologic doses to promote fusion in humans, and are quite expensive. Gene therapy may represent the easiest method for the application of bone-forming biologic agents to promote spinal fusion. Both in vivo and ex vivo techniques of delivery of therapeutic genes have been used effectively to promote fusion in lower animals. Considerable research is required to identify gene therapy techniques and vectors with acceptable safety profiles and high fusion rates.
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ABSTRACT: Anterior cervical discectomy with fusion is a common surgical procedure for patients suffering pain and/or neurological deficits and unresponsive to conservative management. For decades, autologous bone grafted from the iliac crest has been used as a substrate for cervical arthrodesis. However patient dissatisfaction with donor site morbidity has led to the search for alternative techniques. We present a literature review examining the progress of available grafting options as assessed in human clinical trials, considering allograft-based, synthetic, factor- and cell-based technologies.European Spine Journal 04/2009; 18(4):449-464. DOI:10.1007/s00586-008-0878-4 · 2.47 Impact Factor
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ABSTRACT: THE IDEAL GRAFT material to promote spinal fusion should possess osteoconductive, osteoinductive, and osteogenic properties. Although autogenous bone graft has all three qualities and is the standard for comparison, research has focused on finding alternatives that have similar efficacy but not the morbidities associated with graft donor sites. Efforts have focused on various osteoconductive scaffolds and introduction of osteoinductive proteins, including bone morphogenetic protein. Recently, interest in using osteoprogenitor cells, or osteogenesis, for spinal fusion has increased. Bone marrow aspiration allows the introduction of mesenchymal stem cells and ultimately osteoblasts to promote fusion. Preclinical studies suggest that the addition of osteoprogenitor cells to various osteoconductive materials results in a fusion rate similar to that of autograft. There is growing recognition that local gene therapy has the benefit of delivering therapeutic genes that encode novel osteoinductive proteins. Gene delivery offers an alternative to local implantation of recombinant protein, which typically requires high doses of the protein to result in a sufficient osteoinductive response. The findings of animal studies demonstrate that gene therapy results in sustained and regulated production of desired osteoinductive proteins and is efficacious in promoting spinal fusion; however, before treatment in humans can be undertaken, obstacles such as the safety profile, host immune response, transfection rates with insufficient transgene expression, and imprecise control of the timing of transgene expression must be overcome. In this review, the authors summarize the latest research efforts under way to promote spinal fusion with osteoprogenitor cells and gene therapy and discuss the clinical implications of these treatments.Neurosurgery 10/2008; 63(3):380-91; discussion 391-2. DOI:10.1227/01.NEU.0000324990.04818.13 · 3.03 Impact Factor
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ABSTRACT: Object Iliac crest autograft has traditionally been considered the gold standard for lumbar spine fusion, though it is not without drawbacks related to harvesting site pain and other complications. Bone graft alternatives, such as recombinant human bone morphogenetic protein 2 (rh-BMP2), are now widely used but also have unique risk profiles and substantially increase costs. The purpose of the current study was to compare the efficacy of rh-BMP2 and synthetic silicate calcium phosphate (SiCaP) as bone graft substitutes on fusion rates and clinical outcomes in patients undergoing single-level lumbar stand-alone extreme lateral interbody fusion (XLIF).Methods A prospective, randomized, controlled, clinical, and radiographic study was performed at a single institution. Thirty patients with L4-L5 degenerative disc disease (DDD) were enrolled. Patients were randomized into one of two groups, 15 underwent lumbar single-level stand-alone XLIF using SiCaP, and 15 using rh-BMP2. Clinical and radiographic results were compared between the study groups. Pain (visual analogue scale) and disability (Oswestry disability index) were assessed preoperatively and at postoperative weeks 1 and 6 and postoperative months 3, 6, 12, 24, and 36. Radiographic evaluations were performed at 6, 12, 24, and 36 months. Neurological examinations and adverse events were recorded at each visit.Results No intraoperative complications were observed in either treatment group, and clinical outcomes were similarly improved between bone graft substitutes from baseline to 36 months postoperative. Complications were transient hip flexion weakness (13%), insufficient indirect decompression (7%), subsidence (17%), excessive bone formation (4%), and adjacent segment disease (14%). Complication rates between the groups were similar, though with slightly more instances of subsidence in the SiCaP group and higher rates of excessive bone formation and adjacent segment disease in the rh-BMP2 group. Rates of fusion at different time points were different between the groups, with the SiCaP patients progressing more slowly toward solid fusion. However, at 36 months, 100% of patients undergoing XLIF achieved solid fusion.Conclusions In stand-alone XLIF, SiCaP and rhBMP-2 bone graft substitutes both resulted in complete long-term fusion. rhBMP-2, however, seemed to result in more rapid early postoperative fusion, though with one instance of excessive bone formation in one patient that required subsequent surgical intervention.02/2013; 74(6). DOI:10.1055/s-0032-1333420