The use of bone morphogenetic protein—6 gene therapy for percutaneous spinal fusion in rabbits

Laurent, Jeffrey J.; Webb, K. Michael; Beres, Elisa J.; McGee, Kevin M.; Li, Jinzhong; Rietbergen, Bert van; Helm, Gregory A.

doi:10.3171/spi.2004.1.1.0090

Cited by 23 publications

(10 citation statements)

References 34 publications

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“…[16][17][18][19] We previously demonstrated that MSCs overexpressing a BMP gene could be effectively used to induce spine fusion in a mouse model. 20,21 The BMP gene can be introduced into a cell in a variety of ways, including viral 22,23 and nonviral methods. 21,24 MSCs can be isolated from various adult tissues, such as bone marrow and adipose tissue, 25 following common procedures such as liposuction.…”

Section: Introductionmentioning

confidence: 99%

Genetically Modified Mesenchymal Stem Cells Induce Mechanically Stable Posterior Spine Fusion

Sheyn

Rüthemann

Mizrahi

et al. 2010

Tissue Engineering Part A

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Most spine fusion procedures involve the use of prosthetic fixation devices combined with autologous bone grafts rather than biological treatment. We had shown that spine fusion could be achieved by injection of bone morphogenetic protein-2 (BMP-2)-expressing mesenchymal stem cells (MSCs) into the paraspinal muscle. In this study, we hypothesized that posterior spinal fusion achieved using genetically modified MSCs would be mechanically comparable to that realized using a mechanical fixation. BMP-2-expressing MSCs were injected bilaterally into paravertebral muscles of the mouse lumbar spine. In one control group BMP-2 expression was inhibited. Microcomputed tomography and histological analyses were used to evaluate bone formation. For comparison, a group of mouse spines were bilaterally fused with stainless steel pins. The harvested spines were later tested using a custom four-point bending apparatus and structural bending stiffness was estimated. To assess the degree to which MSC vertebral fusion was targeted and to quantify the effects of fusion on adjacent spinal segments, images of the loaded spine curvature were analyzed to extract rigidity of the individual spinal segments. Bone bridging of the targeted vertebrae was observed in the BMP-2-expressing MSC group, whereas no bone formation was noted in any control group. The biomechanical tests showed that MSC-mediated spinal fusion was as effective as stainless steel pin-based fusion and significantly more rigid than the control groups. Local analysis showed that the distribution of stiffness in the MSC-based fusion group was similar to that in the steel pin fusion group, with the majority of spinal stiffness contributed by the targeted fusion at L3-L5. Our findings demonstrate that MSC-induced spinal fusion can convey biomechanical rigidity to a targeted segment that is comparable to that achieved using an instrumental fixation.

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Section: Introductionmentioning

confidence: 99%

Genetically Modified Mesenchymal Stem Cells Induce Mechanically Stable Posterior Spine Fusion

Sheyn

Rüthemann

Mizrahi

et al. 2010

Tissue Engineering Part A

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“…Adenoviral BMP-6 vector construct showed induction of local bone tissue deposition and fusion after multiple level percutaneous injections in the spine of rabbits (12). the same study also demonstrates that BMP-6 gene therapy can induce bone formation in immunocompetent animals, even when administered with an antigenic vector.…”

Section: Mitogensmentioning

confidence: 48%

Biotechnologies in the Treatment of Degenerative Disc Disease of the Cervical Spine

Ferdinandov

Tsekov

Bussarsky

et al. 2012

Biotechnology & Biotechnological Equipment

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“…The genetic modification of MSCs by transducing them with genes capable of regulating the expression and secretion of osteoinductive factors has been employed in an attempt to promote bone formation in spinal arthrodesis and to overcome the complications associated with the local delivery of rhBMPs. Gene delivery is achieved by using a vector (viral or nonviral) through either an in vivo approach, involving the direct introduction of the target gene-containing vector to the fusion site, as illustrated by research from Helm's group [93][94][95], or an ex vivo approach, involving the harvesting and optional culture expansion of MSCs prior to gene transduction.The transduction of BMSCs with genes encoding BMP-2 [96][97][98][99][100], BMP-4 [101], BMP-6 [94], BMP-7 [102], BMP-9 [93,103], LIM mineralization protein [104] and the osteoinductive factor Nell-1 [105] have all successfully been shown to induce spinal fusion in small animal studies. In addition, the transduction of adipose tissue-derived MSCs with BMP-expressing genes has also been shown to promote bone formation in both small and large animal spinal models [106][107][108] with spinal fusion rates comparable to those achieved with genetically modified BMSCs [109].…”

Section: Tissue Engineering Strategiesmentioning

confidence: 99%

Tissue Engineering Strategies in Spinal Arthrodesis: The Clinical Imperative and Challenges to Clinical Translation

et al. 2012

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Skeletal disorders requiring the regeneration or de novo production of bone present considerable reconstructive challenges and are one of the main driving forces for the development of skeletal tissue engineering strategies. The skeletal or mesenchymal stem cell is a fundamental requirement for osteogenesis and plays a pivotal role in the design and application of these strategies. Research activity has focused on incorporating the biological role of the mesenchymal stem cell with the developing fields of material science and gene therapy in order to create a construct that is not only capable of inducing host osteoblasts to produce bone, but is also osteogenic in its own right. This review explores the clinical need for reparative approaches in spinal arthrodesis, identifying recent tissue engineering strategies employed to promote spinal fusion, and considers the ongoing challenges to successful clinical translation.

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The use of bone morphogenetic protein—6 gene therapy for percutaneous spinal fusion in rabbits

Abstract: The results of this study show that an anatomically precise fusion can be accomplished by percutaneous administration of gene therapy. The next step in these studies will be extension of the technique to nonhuman primates and eventually to human clinical studies.

Cited by 23 publications

References 34 publications

Genetically Modified Mesenchymal Stem Cells Induce Mechanically Stable Posterior Spine Fusion

Genetically Modified Mesenchymal Stem Cells Induce Mechanically Stable Posterior Spine Fusion

Biotechnologies in the Treatment of Degenerative Disc Disease of the Cervical Spine

Tissue Engineering Strategies in Spinal Arthrodesis: The Clinical Imperative and Challenges to Clinical Translation

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