Delayed administration of adenoviral BMP-2 vector improves the formation of bone in osseous defects

Betz, Oliver B.; Betz, Volker M.; Nazarian, Ara; Egermann, Marcus; Gerstenfeld, Louis C.; Einhorn, Thomas A.; Vrahas, Mark; Bouxsein, Mary L.; Evans, Christopher H.

doi:10.1038/sj.gt.3302956

Cited by 106 publications

(80 citation statements)

References 25 publications

(27 reference statements)

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“…Adenoviral vectors are attractive because both dividing and nondividing cells can be transduced, and there is only short-term production of the gene of BMPs which meet the needs of bone formation. So, a number of laboratories have evaluated the potential of adenoviral BMP-2 to promote spinal fusion in a variety of preclinical models, 27,28 but little research has been done to evaluate the adeno-BMP7 to enhance healing of segmental weight-bearing bone defects. Adeno-BMP7-transduced BMSCs could express BMP7 up to 2-6 weeks, 29,30 inducing the implanted BMSCs and peripheral MSCs to differentiate into osteoblasts, trigger bone regeneration, and repair the defects.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Bone induction via endochondral ossification was observed in hindlimb muscle of immunocompetent rats (101,102) Viral particles delivered on hydroxyapatite scaffold to the back muscles of immunocompetent rats led to bone formation (103) Bone formation in thigh muscle after delivery of a tetracycline-sensitive expression system was observed in mice only when a tetracycline analogue was administered (153) Orthotopic AV Increased regeneration in a mandibular distraction osteogenesis model in rats (154) Increased bone regeneration in an osteoporotic fracture model in tibia of sheep (155) Bone formation or increased regeneration was observed in several defect models, including a critical-size mandibular defect, (33) critical-size nasal defect in athymic nude mice, (156) rib defect in horses, (157) metatarsal defect in horses, (158) and femoral critical-size defect in rats (159) Injected AVs led to partial regeneration of critical-size calvarial defects in rats, with a more vigorous response when particles were delivered in a gelatin scaffold (117) Healing of iliac crest critical-size defects in sheep was delayed compared with no treatment when viral particles were injected to injury site (160) Bone formation was observed in a dental model in immunocompetent dogs (107) Enhanced cartilage and subchondral bone was observed in femur condyle defect in immunocompetent ponies (161) Delaying administration of viral particles improved healing of femur critical-size defects in rats (162) …”

Section: Aavmentioning

confidence: 99%

Realizing the potential of gene-based molecular therapies in bone repair

Rose

Uludağ

2013

Journal of Bone and Mineral Research

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A better understanding of osteogenesis at genetic and biochemical levels is yielding new molecular entities that can modulate bone regeneration and potentially act as novel therapies in a clinical setting. These new entities are motivating alternative approaches for bone repair by utilizing DNA-derived expression systems, as well as RNA-based regulatory molecules controlling the fate of cells involved in osteogenesis. These sophisticated mediators of osteogenesis, however, pose unique delivery challenges that are not obvious in deployment of conventional therapeutic agents. Viral and nonviral delivery systems are actively pursued in preclinical animal models to realize the potential of the gene-based medicines. This article will summarize promising bone-inducing molecular agents on the horizon as well as provide a critical review of delivery systems employed for their administration. Special attention was paid to synthetic (nonviral) delivery systems because they are more likely to be adopted for clinical testing because of safety considerations. We present a comparative analysis of dose-response relationships, as well as pharmacokinetic and pharmacodynamic features of various approaches, with the purpose of clearly defining the current frontier in the field. We conclude with the authors' perspective on the future of genebased therapy of bone defects, articulating promising research avenues to advance the field of clinical bone repair. © 2013 American Society for Bone and Mineral Research. KEY WORDS: OSTEOGENESIS; BIOENGINEERING; MOLECULAR PATHWAYS; GENE-BASED THERAPYClinical Need for New Bone-Regeneration Strategies N early 2.2 million bone grafts are performed worldwide annually (1) and up to 20% of fractures are hampered by impaired healing. (2) The economic impact of nonunions is enormous, with the cost of spinal fusions alone reaching $20 billion annually. (3) The gold standard for repair of large segmental defects remains autologous grafts, where bone harvested from a non-weight-bearing site, usually the iliac crest, is used to repair defects. Bone grafts, however, are limited in several aspects, including potency of the grafts and the physiological detriment resulting from harvest surgery. Allografts are alternatively employed, where donor tissue is used to repair the defect, but the risk of disease transmission is always a concern. Allografts are extensively processed to reduce this risk, but osteopotency of the graft could be decreased in this way. (4) Demineralized bone matrix derived from decalcified bone can similarly act as a substitute; its potency, however, is variable and depends on the processing conditions. Synthetic scaffolds have been used to provide a hospitable environment for new bone formation. Scaffolds have been constructed from the organic (collagen) and inorganic (hydroxyapatite [HA]) components of bone, but such scaffolds are incapable of inducing osteogenesis on their own and they are more suitable for smaller defects.Osteogenic proteins are frequently employed to render ost...

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“…Because the biology of a fracture site evolves, Betz et al 32 injected Ad.BMP-2 into an experimental rat segmental defect at different times after surgery. They noted a marked increase in repair when the administration of vector was delayed for 5-10 days.…”

Section: Advances In Bone Healingmentioning

confidence: 99%