Stimulation of new bone formation by direct transfer of osteogenic plasmid genes.

Fang, Jianming; Zhu, Yao Yao; Smiley, Elizabeth; Bonadio, Jeffrey; Rouleau, Jeffrey P.; Goldstein, Steven A.; McCauley, Laurie K.; Davidson, Beverly L.; Roessler, Blake J.

doi:10.1073/pnas.93.12.5753

Cited by 471 publications

(293 citation statements)

References 30 publications

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“…The first strategy involves a gene-activated matrix, whereby plasmid DNA including the cDNA for an osteoinductive gene is suspended in the matrix and the DNA is taken up by cells when they enter the matrix [17].…”

Section: Gene Therapymentioning

confidence: 99%

Osteoinductive bone graft substitutes

2000

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Section: Gene Therapymentioning

confidence: 99%

Osteoinductive bone graft substitutes

2000

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“…(47,49) Based on estimated defect volumes, the concentration of pDNA required for efficacy borders that of protein in clinical therapies (0.9 to 1.5 mg/mL). The need for more effective synthetic carriers calls for a better understanding of pharmacokinetic and pharmacodynamic issues affecting gene medicines.…”

Section: Pharmacokinetics and Pharmacodynamics Of Gene Deliverymentioning

confidence: 99%

“…A high pDNA dose (500 µg) was also needed for this purpose. The specific role of the collagen in pDNA delivery was unknown, but it may retain the pDNA at the injection site longer, rather than facilitating intracellular uptake/trafficking.In one of the earliest studies, BMP-4 plasmid (500 to 1000 mg) delivered in a collagen scaffold in a rat critical femur model (47) led to defect bridging after 9 weeks compared with fibrous tissue seen with collagen sponges alone. A combination of a PTH1-34 and BMP-4 plasmid led to accelerated healing such that the bone defect was bridged in 4 weeks.…”

mentioning

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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“…This cDNA was placed into a collagen matrix forming a 'gene-activated matrix' (GAM), which resulted in bone formation. 34 Although PTH may not be the ideal molecule for local bone induction in ectopic or intramuscular sites, this study did Several research groups have worked with the human BMP-2 cDNA delivered with a replication-deficient recombinant adenoviral vector. The Ad-hBMP-2 construct when transduced into murine stromal, 35 C2C12 myoblasts, 36 primary muscle-derived cells, 37,38 or mesenchymal progenitor cells 39,40 induced bone when injected intramuscularly in rodent muscle beds, rodent critical sized skull defects, 41,42 or in a mouse radial segmental defect models.…”

Section: Introductionmentioning

confidence: 98%