FIBROUS DYSPLASIA OF BONE – TRANSGENIC MODELS OF DISEASES, AND MODELS OF THERAPY

Polyostotic Fibrous Dysplasia/McCune Albright syndrome is a genetic disease caused by mutations that arise early in the embryo. The involvement of the skeleton is the most serious aspect of the disease, and causes multiple and repeated fractures that begin in early infancy, and deformities of the skull, face, limbs, and trunk. In its most severe forms, the disease is crippling and may result in wheelchair confinement, blindness or deafness, and in rare cases may be lethal due to respiratory complications of the skeletal lesions. At present, there is no rational therapy of proven efficacy with respect to the correction of the bone abnormalities. The bone lesions result from the presence of the mutation in bone−forming cells (osteoblasts) and in their progenitor cells (stem cells). To correct the bone disease, one should be able to replace, or genetically correct, the mutated bone cells and their progenitor (stem) cells, or at the least, to clearly understand the metabolic derangement caused,within cells, by the mutation, so that effective drugs could be designed. To understand these derangements, and to develop and test either new drugs, or highly innovative therapeis such as cell and gene therapy, animal models that directly reproduce the disease are strictly required, actually indispensabile, and must be generated by the creation of mice carrying the same mutations as those found in patients. The studies proposed herein aim at completing the development and the characterization of such models, and at their use for the development and testing of therapies based on stem cell and gene correction, as well as for the mechanistic understanding of how bone lesions develop and can be prevented or corrected.