Ex vivo gene therapy for skeletal regeneration in cranial defects compromised by postoperative radiotherapy.
Because radiation remains a common postoperative treatment for head and neck cancers, it is critical to determine whether new bone-regenerative approaches are effective for healing craniofacial defects challenged by therapeutic doses of radiation. The objective of this study was to determine whether the deleterious effects of radiotherapy could be overcome by ex vivo gene therapy to heal craniofacial defects. Rat calvarial critical-sized defects were treated with either an inlay calvarial bone graft or syngeneic dermal fibroblasts transduced ex vivo with an adenovirus engineered to express bone morphogenetic protein 7 (BMP-7), a morphogen known to stimulate bone formation. Two weeks postoperatively, either no radiation or a single 12-Gy radiation dose was delivered to the operated area and the tissue was harvested 4 weeks later. None of the inlay bone grafts healed at the wound margins of either the radiated or nonradiated sites. In contrast, bone was successfully regenerated when using an ex vivo gene therapy approach. More bone formed in the nonradiated group as determined by the percentage of defect surface covered (87 +/- 4.1 versus 65 +/- 4.7%; p = 0.003) and percentage of defect area filled by new bone (60 +/- 5.9 versus 32 +/- 2.7%; p = 0.002). Although the effects of radiation on the wound were not completely overcome by the gene therapy approach, bone regeneration was still successful despite the radiation sensitivity of the fibroblasts. These results indicate that BMP-7 ex vivo gene therapy is capable of successfully regenerating bone in rat calvarial defects even after a therapeutic dose of radiation. This approach may represent a new strategy for regenerating skeletal elements lost due to head and neck cancer.
Nussenbaum
Brian
B
Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Rutherford
R Bruce
RB
Teknos
Theodoros N
TN
Dornfeld
Kenneth J
KJ
Krebsbach
Paul H
PH
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D001861:Bone Regeneration; D016025:Bone Transplantation; D003399:Craniotomy; D020405:Dermis / Q000166:cytology; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects / Q000637:transplantation; D015316:Genetic Therapy; D005822:Genetic Vectors; D006258:Head and Neck Neoplasms / Q000532:radiotherapy / Q000601:surgery / Q000628:therapy; D006801:Humans; D019426:Integrases / Q000235:genetics; D011184:Postoperative Period; D011836:Radiation Tolerance; D011878:Radiotherapy / Q000009:adverse effects; D051381:Rats; D011916:Rats, Inbred F344; D012886:Skull / Q000033:anatomy & histology / Q000502:physiology / Q000528:radiation effects*; D014161:Transduction, Genetic; D016212:Transforming Growth Factor beta; D014182:Transplantation, Autologous; D014764:Viral Proteins / Q000235:genetics
C525819:BMP7 protein, human; C525821:Bmp7 protein, rat; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D016212:Transforming Growth Factor beta; D014764:Viral Proteins; C045073:Cre recombinase; D019426:Integrases