POLYOSTOTIC FIBROUS DYSPLASIA/MCCUNE ALBRIGHT SYNDROME: MODELS OF DISEASE, MODELS OF INTERVENTION

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 repeated fractures that begin in early infancy, 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. These 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. These could be obtained, in many cases, from the patient itself, since some normal cells are retained in patients' tissues in spite of the presence of the mutation in other cells. To develop and test this kind of therapies (and many others), animal models that directly reproduce the disease are strictly required and must be generated by the creation of mice carrying the same mutations as those found in patients. The studies proposed herein aim at creating such models, and at their use for the development and testing of therapies based on stem cell and gene correction.