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: 12.71). 03/2012; 64(12):1320-30. DOI: 10.1016/j.addr.2012.03.007
Source: PubMed

ABSTRACT 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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    • "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.
    The Scientific World Journal 01/2014; 2014(406159):406159. DOI:10.1155/2014/406159 · 1.73 Impact Factor
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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.
    Biomaterials 01/2014; 35(9). DOI:10.1016/j.biomaterials.2013.12.039 · 8.31 Impact Factor
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    ABSTRACT: Osteoporosis, a major public health burden, is associated with increased fracture risk. Fracture healing in osteoporosis is delayed, with reduced callus formation and impaired biomechanical properties of newly formed bone leading to high risk of fixation failure. Adenoviral gene transfer of bone morphogenetic protein-2 (BMP-2) has been shown to enhance fracture healing. This study evaluated the ability of gene transfer to enhance bone healing in osteoporosis. An established sheep model of osteoporosis with well-characterized alterations in fracture healing was used. Osteotomies were created surgically in the tibias of adult female sheep and monitored for 8 weeks, using radiographic, biomechanical, and histological methods. For pilot experiments, primary ovine osteoblasts and mesenchymal stem cells were transduced with a recombinant adenovirus carrying BMP-2 cDNA (Ad.BMP-2). Large increases in alkaline phosphatase production and mineralization confirmed the ability of human BMP-2 to stimulate osteoblastic differentiation in sheep. In vivo bending stiffness measurements during fracture healing as well as ex vivo torsional stiffness measurements demonstrated stiffer callus tissue after treatment with Ad.BMP-2. The differences were found mainly in the early fracture-healing period. Computed tomography demonstrated that animals receiving the BMP-2 cDNA had larger cross-sectional callus area and higher callus density. Histological examination of the tibias confirmed enhanced callus formation. Direct, local adenoviral delivery of an osteogenic gene thus led to enhanced healing of fractures in an ovine model of osteoporosis. These promising data encourage the further development of genetic approaches to enhance bone healing in patients suffering osteoporosis-associated fractures.
    Human Gene Therapy 06/2006; 17(5):507-17. DOI:10.1089/hum.2006.17.507 · 3.62 Impact Factor
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