Remodeling of cortical bone allografts mediated by adherent rAAV-RANKL and VEGF gene therapy

• Published in: Nature medicine Vol. 11; no. 3; pp. 291 - 297
• Main Authors: Schwarz, Edward M, Ito, Hiromu, Koefoed, Mette, Tiyapatanaputi, Prarop, Gromov, Kirill, Goater, J Jeffrey, Carmouche, Jonathan, Zhang, Xinping, Rubery, Paul T, Rabinowitz, Joseph, Samulski, R Jude, Nakamura, Takashi, Soballe, Kjeld, O'Keefe, Regis J, Boyce, Brendan F
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.03.2005
• Subjects: Animals; Bone Remodeling - physiology; Bone Transplantation; Carrier Proteins - genetics; Carrier Proteins - physiology; Dependovirus - genetics; Femur; Fractures; Freeze Drying; Gene expression; Gene therapy; Genetic Therapy; Genetic Vectors; Membrane Glycoproteins - genetics; Membrane Glycoproteins - physiology; Mice; Mice, Inbred C57BL; Molecular Sequence Data; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Transduction, Genetic; Transplantation, Homologous; Transplants & implants; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - physiology; Wound Healing; Denmark; United States > US; Aarhus Denmark
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm1190

Structural allograft healing is limited because of a lack of vascularization and remodeling. To study this we developed a mouse model that recapitulates the clinical aspects of live autograft and processed allograft healing. Gene expression analyses showed that there is a substantial decrease in the genes encoding RANKL and VEGF during allograft healing. Loss-of-function studies showed that both factors are required for autograft healing. To determine whether addition of these signals could stimulate allograft vascularization and remodeling, we developed a new approach in which rAAV can be freeze-dried onto the cortical surface without losing infectivity. We show that combination rAAV-RANKL- and rAAV-VEGF-coated allografts show marked remodeling and vascularization, which leads to a new bone collar around the graft. In conclusion, we find that RANKL and VEGF are necessary and sufficient for efficient autograft remodeling and can be transferred using rAAV to revitalize structural allografts.