GENE THERAPY AND OSTEOGENESIS IMPERFECTA: USE OF THE NOVEL PROTEIN LMP TO ENHANCE BONE HEALING IN CONGENITAL DISEASES

Our objective is to develop improved methods for treating the bone fractures associated with Osteogenesis Imperfecta (OI) by gene and protein based therapies. The successful of these studies should result in enhancing of bone healing without the need for surgical intervention. OI is a dominant congenital disease characterized by bone fragility in which many different mutations and genetic defects have been identified. Thus a gene therapy approach for treating the different genetic defects associated with OI is not actually feasible. The focus of this application is to develop novel approaches to treat bone fractures, the major complication associated with brittle bone diseases. Gene therapy has been already used to treat bone fractures and local gene transfer of BMPs has been shown to increase the rate and efficiency of bone healing. Recently, a novel gene and his proteic product, termed Lim Mineralization Protein (LMP), has been described. Gene transfer of LMP has been demonstrated to induce expression of a class of genes, including BMPs, involved in bone formation. we want evaluate the ability of LMP to facilitate bone differentiation in cultured stem cells and to facilitate bone healing in non-union fractures. In addition, the ability of the minimal functional domain of LMP, fused to a protein transduction domain, to stimulate bone formation as recombinant protein will be evaluated both in cell culture and in vivo. These experiments could result in improved methods for enhancing bone healing for treatment of pathologies associated with OI without the need for surgical intervention, specially in children with severe form and an high numbers of fractures.