Fibrous Dysplasia of bone/McCune-Albright Syndrome (FD/MAS, OMIM#174800) is a disabling consequence of post-zygotic, gain-of-function mutations of the GNAS gene, encoding the alpha subunit of the stimulatory G protein, Gsa. FD represents the most severe and crippling aspect within the spectrum of skeletal, endocrine and cutaneous lesions that characterize the McCune-Albright syndrome, but also occurs (in association with the same mutations) in non-MAS patients as an isolated, monostotic or polyostotic disease. Current therapies for FD are merely palliative. The genetic nature of the disease calls for the development of radical therapeutic interventions based on gene correction or cell therapy, which, in turn, require the development of suitable experimental models of the disease. Capitalizing on the FD transgenic models that we have previously generated, we have recently developed a novel Immunodeficient/Fibrous Dysplasia (SCID/FD) transgenic mouse strain. Of note, this new mouse strain represents the first-in-class immunodeficient transgenic model of a human skeletal disease. In this project, we will first perform a detailed radiographic and histological analysis of the skeletal lesions of our new SCID/FD mice in comparison with those of FD mice. Then, we will use our SCID/FD mice for preliminary cell therapy studies for FD based on local transplantation of skeletal stem cells isolated from membrane-Tomato/membrane-GFP (mT/mG) dual fluorescent reporter mice.
Immunodeficient transgenic models are an essential tool for developing cell therapies, especially for diseases of mesodermal tissues. Currently, there are no available models of human skeletal diseases in immunodeficient mice. Our SCID/FD transgenic mouse, which will be characterized and validated in this project, will allow for the first time a detailed analysis of the behavior and regenerative potential of different populations of skeletal stem cells (e.g. cells from reporter mice, human natural skeletal stem cells, human iPSC-derived skeletal stem cells) in FD. It will also allow to define many critical technical aspects related to the use of human skeletal stem cells (e.g. local vs systemic injection, number of cells to be transplanted, type of carrier to be used in local delivery, etc) that go beyond FD and are of general interest in the bone field.
Furthermore, our studies will help to clarify if, and to what extent, the clinical expression of FD is modulated by the immune system. While a role for skeletal stem cells in the pathogenesis of the disease has been established many years ago, little is known on the potential direct or indirect modulatory effect of other non-skeletal cell types on its clinical expression. We expect that through the detailed characterization of the skeletal phenotype of the SCID/FD mouse model in comparison with that of the FD mouse model, we will address this issue with regard to immune cells. This, in turn, may have potential implication for the future identification of medical therapies able to affect the natural history of the disease.