Multipotent and pluripotent stem cells for the elucidation and therapy of skeletal disease in mucopolysaccharidoses (MPSs)

Mucopolysaccharidoses (MPSs) are a group of rare genetic disorders, caused by deficiency of the lysosomal enzymes essential for the degradation of molecules named glycosaminoglycans (GAGs). The progressive intracellular accumulation of undegraded GAGs results in gradual deterioration and abnormal function of multiple organs. The clinical condition is generally marked by hepatosplenomegaly, obstructive airway disease complicated by respiratory infections, cardiac failure, progressive mental retardation and musculoskeletal abnormalities known as dysostosis multiplex. For mucopolysaccharidosis type I, which is the most well-known clinical type of these disorders, bone marrow transplantation is one of the most promising treatments available. Unfortunately, this therapy ameliorates the multi-organ morbidity, but not the skeletal manifestations which still deteriorate and impact the quality of life in most transplanted MPS I patients. The general objective of our study is to concentrate upon the skeletal disease typical of MPS patients, through the searching of a possible therapeutic approach and the study of the pathological mechanisms using patient-derived stem cells. Therefore, the first aim of our project is focused on the development of an early therapeutic intervention, exploring the efficacy of a bone marrow transplantation treatment at birth on the mouse model which better represents the typical skeletal disease and evaluating its efficacy especially on the severe skeletal defects. To achieve a better comprehension of the skeletal disease, we plan to characterize patient-derived stem cells, investigating their biologic profile and their capacity to generate bone/bone marrow tissue in a specific in vivo bone formation model recently created.