Ex vivo gene therapy with stromal cells transduced with a retroviral vector containing the BMP4 gene completely heals critical size calvarial defect in rats

Gysin, Reinhard; Je, Wergedal; Mh, Sheng; Kasukawa, Yuji; Miyakoshi, Naohisa; Chen, St; Peng, Hairong; Lau, K.-H. William; Mohan, Subburaman; Baylink, D J

doi:10.1038/sj.gt.3301772

Cited by 106 publications

(68 citation statements)

References 31 publications

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“…46 The bone regeneration data suggest BMP-4 produced in the transfected cells was active and its expression was sustained. Previous studies using either protein or gene therapy usually reported enhanced bone formation over short periods of time, 33,38 while a long-term effect on bone regeneration was achieved in this study. Histological examination of sections from scaffolds incorporating condensed DNA showed active de novo bone formation (woven) structure even at 15 weeks.…”

Section: Discussionmentioning

confidence: 50%

“…24 In addition, BMPs serve as growth factors by stimulating angiogenesis (ie the formation of new capillary vessels from existing host vessels) 28 and proliferation of stem cells from surrounding mesenchymal tissues. [29][30][31] Gene therapy approaches to deliver BMPs to bone defect sites include ex vivo genetic modification of cells that are subsequently transplanted, 20,22,23,26,32,33 injection of viral vectors containing BMP encoding sequences, 21 and plasmid DNA-based approaches. 10 The amount of BMP produced from ex vivo modified cells may be limited by their survival rate after transplantation, which may be especially low in larger defects, and this approach is complex and involves multisteps.…”

Section: Introductionmentioning

confidence: 99%

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Bone regeneration in a rat cranial defect with delivery of PEI-condensed plasmid DNA encoding for bone morphogenetic protein-4 (BMP-4)

et al. 2005

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Section: Discussionmentioning

confidence: 50%

Section: Introductionmentioning

confidence: 99%

Bone regeneration in a rat cranial defect with delivery of PEI-condensed plasmid DNA encoding for bone morphogenetic protein-4 (BMP-4)

et al. 2005

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“…Gysin et al [54] developed an efficient MoMLV-based retroviral system expressing the human BMP4 transgene. The bone formation potential of transduced cells expressing BMP4 was tested by embedding transduced stromal cells in a gelatin matrix that was then placed in a critical size defect in calvariae of syngenic rats.…”

Section: Genementioning

confidence: 99%

“…The proteins included the Escherichia coli β-galactosidase [15,40], GFP [14,18,19] and red fluorescent protein (DsRed) [19], as well as many therapeutic proteins, including coagulation factors VIII [12,16,17] and IX [41][42][43], IL-3 [15,44,45] and IL-7 [46], human growth hormone [41], human erythropoietin (hEPO) [47] and murine erythropoietin (mEPO) [48], arylsulfatase A [49,50], tyrosine hydroxylase GTP cyclohydrolase I [13,51], α-L-iduronidase [52], β-hexosaminidase A [53] and bone morphogenetic protein (BMP) [54]. It remains to be determined how MSCs perform relative to other mammalian expression systems, such as Chinese hamster ovary cells, in terms of transgene expression levels.…”

Section: Mesenchymal Stem Cells As Platforms For Recombinant Protein mentioning

confidence: 99%

Potential of mesenchymal stem cells in gene therapy approaches for inherited and acquired diseases

Reiser

Zhang

Hemenway

et al. 2005

Expert Opinion on Biological Therapy

166

114

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The intriguing biology of stem cells and their vast clinical potential is emerging rapidly for gene therapy. Bone marrow stem cells, including the pluripotent haematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs) and possibly the multipotent adherent progenitor cells (MAPCs), are being considered as potential targets for cell and gene therapy-based approaches against a variety of different diseases. The MSCs from bone marrow are a promising target population as they are capable of differentiating along multiple lineagesn and, at least in vitro, have significant expansion capability. The apparently high self-renewal potential makes them strong candidates for delivering genes and restoring organ systems function. However, the high proliferative potential of MSCs, now presumed to be self-renewal, may be more apparent than real. Although expanded MSCs have great proliferation and differentiation potential in vitro, there are limitations with the biology of these cells in vivo. So far, expanded MSCs have failed to induce durable therapeutic effects expected from a true self-renewing stem cell population. The loss of in vivo self-renewal may be due to the extensive expansion of MSCs in existing in vitro expansion systems, suggesting that the original stem cell population and/or properties may no longer exist. Rather, the expanded population may indeed be heterogeneous and represents several generations of different types of mesenchymal cell progeny that have retained a limited proliferation potential and responsiveness for terminal differentiation and maturation along mesenchymal and non-mesenchymal lineages. Novel technology that allows MSCs to maintain their stem cell function in vivo is critical for distinguishing the elusive stem cell from its progenitor cell populations. The ultimate dream is to use MSCs in various forms of cellular therapies, as well as genetic tools that can be used to better understand the mechanisms leading to repair and regeneration of damaged or diseased tissues and organs.

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“…Therefore, local gene therapy systems have been successfully used to deliver BMPs. [9][10][11] Load-bearing is very important to bone formation, which has been described in classic literature, but many studies on tissue-engineered bone regeneration were conducted at non-load-bearing sites or in defects stabilized with stress-shielding devices. 12,13 In addition, those devices, such as bone plates, usually impede the remodeling of the newly formed bone at the defect site.…”

mentioning

confidence: 99%

Enhanced healing of goat femur‐defect using BMP7 gene‐modified BMSCs and load‐bearing tissue‐engineered bone

Zhu

Dai

Liu

et al. 2009

Journal Orthopaedic Research

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Segmental defect regeneration is still a clinical challenge. In this study, we investigated the feasibility of bone marrow stromal cells (BMSCs) infected with adenoviral vector containing the bone morphogenetic protein 7 gene (AdBMP7) and load-bearing to enhance bone regeneration in a critically sized femoral defect in the goat model. The defects were implanted with AdBMP7-infected BMSCs/coral (BMP7 group) or noninfected BMSCs/coral (control group), respectively, stabilized with an internal fixation rod and interlocking nails. Bridging of the segmental defects was evaluated by radiographs monthly, and confirmed by biomechanical tests. Much callus was found in the BMP7 group, and nails were taken off after 3 months of implantation, indicating that regenerated bone in the defect can be remodeled by loadbearing, whereas after 6 months in control group. After load-bearing, it is about 5 months; the mechanical property of newly formed bone in the BMP7 group was restored, but 8 months in control group. Our data suggested that the BMP7 gene-modified BMSCs and load-bearing can promote bone regeneration in segmental defects. ß

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Ex vivo gene therapy with stromal cells transduced with a retroviral vector containing the BMP4 gene completely heals critical size calvarial defect in rats

Cited by 106 publications

References 31 publications

Bone regeneration in a rat cranial defect with delivery of PEI-condensed plasmid DNA encoding for bone morphogenetic protein-4 (BMP-4)

Bone regeneration in a rat cranial defect with delivery of PEI-condensed plasmid DNA encoding for bone morphogenetic protein-4 (BMP-4)

Potential of mesenchymal stem cells in gene therapy approaches for inherited and acquired diseases

Enhanced healing of goat femur‐defect using BMP7 gene‐modified BMSCs and load‐bearing tissue‐engineered bone

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