Gene therapy for degenerative disc disease

Sobajima, Satoshi; Js, Kim; Gilbertson, LG; Kang, JD

doi:10.1038/sj.gt.3302200

Cited by 92 publications

(62 citation statements)

References 48 publications

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“…Therefore, cell-based therapies should have a potential, in terms of recovery and healing of degenerated IVDs. Unlike gene and molecular therapies, which have problems such as the risks associated with viral gene transfer and growth factor production issues (intellectual property ownership and heavy clinical regulatory requirements) [6], autologous cell-based therapies have the advantages of improved safety and easier regulatory approval. Cell therapies have been tested in animal models with some success for degenerative disc disease [7], and some human clinical trials show an increase in the height of the degenerated disc and a reduction of pain in patients treated with discchondrocyte cells [8].…”

Section: Introductionmentioning

confidence: 99%

Influence of different commercial scaffolds on the in vitro differentiation of human mesenchymal stem cells to nucleus pulposus-like cells

et al. 2011

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Introduction Cell-based therapies for regeneration of the degenerated intervertebral disc (IVD) are an alternative to current surgical intervention. Mesenchymal stem cells (MSCs), in combination with a scaffold, might be ideal candidates for regenerating nucleus pulposus (NP), the pressure-distributing part of the IVD. While the use of growth factors for MSCs differentiation currently receives major attention, in this study we compare the performance of sponge-like matrixes in supporting cell differentiation into NP-like cells. Materials and methods Four types matrixes approved as medical devices for other applications were tested as scaffolds for MSCs: two made of equine or porcine collagen, one of gelatin and one of chitosan. Bone marrowderived human MSCs were seeded in these scaffolds or embedded in alginate, as a three-dimensional control. After five weeks in culture, NP-like differentiation of the cellscaffold constructs was analyzed by qRT-PCR, histology, total DNA quantification, proteoglycan accumulation and immunohistochemistry. Results MSCs in collagen matrixes and gelatin produced more mRNA and proteins of the chondrogenic markers collagen type I, collagen type II (COL2) and aggrecan (ACAN), when compared with cells embedded in alginate or chitosan. Proteoglycan accumulation and cell survival were also higher in collagen and gelatin matrixes. Gene expression results were also confirmed by histological and immunohistochemical staining. In contrast to alginate control, the gene expression of the undesired bone marker osteopontin was lower in all tested groups. In porcine collagen supports, MSC expression ratio between COL2/ ACAN closely resembled the expression of nucleus pulposus cells, but gene expression of recently described NP markers keratin19, PAX1 and FOXF1 was lower. Conclusions Collagen supports provide a readily available, medically approved and effective scaffold for chondrogenic differentiation in vitro, but the phenotype of differentiated MSCs is not yet completely equivalent to that of NP cells.

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Section: Introductionmentioning

confidence: 99%

Influence of different commercial scaffolds on the in vitro differentiation of human mesenchymal stem cells to nucleus pulposus-like cells

et al. 2011

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“…It accounts for 8 million physician visits and 89 million lost work days per year, 1 and it incurs an estimated cost of up to $50 billion annually. 2 Low back pain is caused by intervertebral disc degeneration and other pathological conditions such as spondylosis, scoliosis, spondylolisthesis, tumor, infection, and posttraumatic fracture.…”

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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“…The previous studies have demonstrated extended expression time of marker transgenes mediated by an adenoviral vector in a rabbit lumbar disc model (Nishida et al, 1998;1999;Shimer et al, 2004;Sobajima et al, 2004;Larson III et al, 2006;Kaneyama et al, 2008). Therefore, IVD is an appropriate site for adenovirus-mediated transfer of exogenous genes thereby resulting in production of therapeutic growth factors.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus-mediated GDF-5 promotes the extracellular matrix expression in degenerative nucleus pulposus cells

Luo

Liu

Zhu

et al. 2016

J. Zhejiang Univ. Sci. B

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Abstract:Objective: To construct a recombinant adenovirus vector-carrying human growth and differentiation factor-5 (GDF-5) gene, investigate the biological effects of adenovirus-mediated GDF-5 (Ad-GDF-5) on extracellular matrix (ECM) expression in human degenerative disc nucleus pulposus (NP) cells, and explore a candidate gene therapy method for intervertebral disc degeneration (IDD). Methods: Human NP cells of a degenerative disc were isolated, cultured, and infected with Ad-GDF-5 using the AdEasy-1 adenovirus vector system. On Days 3, 7, 14, and 21, the contents of the sulfated glycosaminoglycan (sGAG), deoxyribonucleic acid (DNA) and hydroxyproline (Hyp), synthesis of proteoglycan and collagen II, gene expression of collagen II and aggrecan, and NP cell proliferation were assessed. Results: The adenovirus was an effective vehicle for gene delivery with prolonged expression of GDF-5. Biochemical analysis revealed increased sGAG and Hyp contents in human NP cells infected by Ad-GDF-5 whereas there was no conspicuous change in basal medium (BM) or Ad-green fluorescent protein (GFP) groups. Only cells in the Ad-GDF-5 group promoted the production of ECM, as demonstrated by the secretion of proteoglycan and up-regulation of collagen II and aggrecan at both protein and mRNA levels. The NP cell proliferation was significantly promoted. Conclusions: The data suggest that Ad-GDF-5 gene therapy is a potential treatment for IDD, which restores the functions of degenerative intervertebral disc through enhancing the ECM production of human NP cells.

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Gene therapy for degenerative disc disease

Cited by 92 publications

References 48 publications

Influence of different commercial scaffolds on the in vitro differentiation of human mesenchymal stem cells to nucleus pulposus-like cells

Influence of different commercial scaffolds on the in vitro differentiation of human mesenchymal stem cells to nucleus pulposus-like cells

Genetically Modified Mesenchymal Stem Cells Induce Mechanically Stable Posterior Spine Fusion

Adenovirus-mediated GDF-5 promotes the extracellular matrix expression in degenerative nucleus pulposus cells

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