Gene therapy approaches to regenerating bone

Skeletal Biotech Laboratory, The Hebrew University, Hadassah Faculty of Dental Medicine, Ein Kerem, Jerusalem, Israel.
Advanced drug delivery reviews (Impact Factor: 15.04). 03/2012; 64(12):1320-30. DOI: 10.1016/j.addr.2012.03.007
Source: PubMed


Bone formation and regeneration therapies continue to require optimization and improvement because many skeletal disorders remain undertreated. Clinical solutions to nonunion fractures and osteoporotic vertebral compression fractures, for example, remain suboptimal and better therapeutic approaches must be created. The widespread use of recombinant human bone morphogenetic proteins (rhBMPs) for spine fusion was recently questioned by a series of reports in a special issue of The Spine Journal, which elucidated the side effects and complications of direct rhBMP treatments. Gene therapy - both direct (in vivo) and cell-mediated (ex vivo) - has long been studied extensively to provide much needed improvements in bone regeneration. In this article, we review recent advances in gene therapy research whose aims are in vivo or ex vivo bone regeneration or formation. We examine appropriate vectors, safety issues, and rates of bone formation. The use of animal models and their relevance for translation of research results to the clinical setting are also discussed in order to provide the reader with a critical view. Finally, we elucidate the main challenges and hurdles faced by gene therapy aimed at bone regeneration as well as expected future trends in this field.

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    • "Regeneration of bone defects is accomplished by cells, bioactive factors, and ECM, which continue to work together to regulate the proliferation, differentiation, and migration of osteoprogenitor cells. Recent advances in cell and molecular biology have enabled researchers in the BTE field to integrate stem cells with gene medicine.4,23,24 Herein, we applied PEI–al/pBMP-2 complexes to fabricate a BMP-2 protein-producing cell sheet, which is an organic combination of cells, bioactive factors, and ECM. "
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    ABSTRACT: Regeneration of large bone defects is a common clinical problem. Recently, stem cell sheet has been an emerging strategy in bone tissue engineering. To enhance the osteogenic potential of stem cell sheet, we fabricated bone morphogenetic protein 2 (BMP-2) gene-engineered cell sheet using a complex of polyethylenimine-alginate (PEI-al) nanocomposites plus human BMP-2 complementary(c)DNA plasmid, and studied its osteogenesis in vitro and in vivo. PEI-al nanocomposites carrying BMP-2 gene could efficiently transfect bone marrow mesenchymal stem cells. The cell sheet was made by culturing the cells in medium containing vitamin C for 10 days. Assays on the cell culture showed that the genetically engineered cells released the BMP-2 for at least 14 days. The expression of osteogenesis-related gene was increased, which demonstrated that released BMP-2 could effectively induce the cell sheet osteogenic differentiation in vitro. To further test the osteogenic potential of the cell sheet in vivo, enhanced green fluorescent protein or BMP-2-producing cell sheets were treated on the cranial bone defects. The results indicated that the BMP-2-producing cell sheet group was more efficient than other groups in promoting bone formation in the defect area. Our results suggested that PEI-al nanocomposites efficiently deliver the BMP-2 gene to bone marrow mesenchymal stem cells and that BMP-2 gene-engineered cell sheet is an effective way for promoting bone regeneration.
    Full-text · Article · May 2014 · International Journal of Nanomedicine
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    • "In addition, the overwhelming amount of studies that have been investigating the molecular scenario orchestrating osteogenesis and bone healing, provided new osteoinductive molecules to be tested as potential drugs in spine surgery. On the other hand, cell-based gene therapy approaches based on engineered-osteoinductive cells allowed achieving the most convincing results in terms of bone healing and spine fusion in animal models [14] [15] [16] [17] [18] [19]. Actually, genetically engineered cells are believed to maintain physiologic doses of a gene product for a sustained period once inoculated into the selected anatomical site, facilitating an efficient bone healing [20]. "
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    ABSTRACT: Bone fusion represents a challenge in the orthopedics practice, being especially indicated for spine disorders. Spinal fusion can be defined as the bony union between two vertebral bodies obtained through the surgical introduction of an osteoconductive, osteoinductive, and osteogenic compound. Autogenous bone graft provides all these three qualities and is considered the gold standard. However, a high morbidity is associated with the harvest procedure. Intensive research efforts have been spent during the last decades to develop new approaches and technologies for successful spine fusion. In recent years, cell and gene therapies have attracted great interest from the scientific community. The improved knowledge of both mesenchymal stem cell biology and osteogenic molecules allowed their use in regenerative medicine, representing attractive approaches to achieve bone regeneration also in spinal surgery applications. In this review we aim to describe the developing gene- and cell-based bone regenerative approaches as promising future trends in spine fusion.
    Full-text · Article · Jan 2014 · The Scientific World Journal
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    • "e l s e v i e r. co m/ lo ca t e / b i o m a t e ri a l s regardless of the treatment regimen, dose, or delivery method. The second strategy utilizes viral and/or non-viral targeted osteogenic or angiogenic gene delivery approaches [16] [17]. While a few of the gene transfer methods for critical defect healing have reached orthopedic pre-clinical trials, there remain significant regulatory, efficacy , and safety concerns with the use of viral agents or genetically altered cells for implantation into patients. "
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    ABSTRACT: Structural bone allografts are widely used in the clinic to treat critical sized bone defects, despite lacking the osteoinductive characteristics of live autografts. To address this, we generated revitalized structural allografts wrapped with mesenchymal stem/progenitor cell (MSC) sheets, which were produced by expanding primary syngenic bone marrow derived cells on temperature-responsive plates, as a tissue-engineered periosteum. In vitro assays demonstrated maintenance of the MSC phenotype in the sheets, suggesting that short-term culturing of MSC sheets is not detrimental. To test their efficacy in vivo, allografts wrapped with MSC sheets were transplanted into 4-mm murine femoral defects and compared to allografts with direct seeding of MSCs and allografts without cells. Evaluations consisted of X-ray plain radiography, 3D microCT, histology, and biomechanical testing at 4- and 6-weeks post-surgery. Our findings demonstrate that MSC sheets induce prolonged cartilage formation at the graft-host junction and enhanced bone callus formation, as well as graft-host osteointegration. Moreover, a large periosteal callus was observed spanning the allografts with MSC sheets, which partially mimics live autograft healing. Finally, biomechanical testing showed a significant increase in the structural and functional properties of MSC sheet grafted femurs. Taken together, MSC sheets exhibit enhanced osteogenicity during critical sized bone defect repair, demonstrating the feasibility of this tissue engineering solution for massive allograft healing.
    Full-text · Article · Jan 2014 · Biomaterials
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