Gene therapy for bone healing: lessons learned and new approaches.

Although gene therapy has its conceptual origins in the treatment of Mendelian disorders, it has potential applications in regenerative medicine, including bone healing. Research into the use of gene therapy for bone healing began in the 1990s. Prior to this period, the highly osteogenic proteins bone morphogenetic protein (BMP)-2 and -7 were cloned, produced in their recombinant forms and approved for clinical use. Despite their promising osteogenic properties, the clinical usefulness of recombinant BMPs is hindered by delivery problems that necessitate their application in vastly supraphysiological amounts. This generates adverse side effects, some of them severe, and raises costs; moreover, the clinical efficacy of the recombinant proteins is modest. Gene delivery offers a potential strategy for overcoming these limitations. Our research has focused on delivering a cDNA encoding human BMP-2, because the recombinant protein is Food and Drug Administration approved and there is a large body of data on its effects in people with broken bones. However, there is also a sizeable literature describing experimental results obtained with other transgenes that may directly or indirectly promote bone formation. Data from experiments in small animal models confirm that intralesional delivery of BMP-2 cDNA is able to heal defects efficiently and safely while generating transient, local BMP-2 concentrations 2-3 log orders less than those needed by recombinant BMP-2. The next challenge is to translate this information into a clinically expedient technology for bone healing. Our present research focuses on the use of genetically modified, allografted cells and chemically modified messenger RNA.