Development of a technological platform to study the pathophysiological mechanisms of skeletal damage and the impact of ex-vivo gene therapy in MPSIH and in other LSDs with skeletal involvement

Mucopolysaccharidosis type I Hurler (MPSIH) is a lysosomal storage disorder (LSD) caused by alpha-L-iduronidase (IDUA) enzyme deficiency, involved in the degradation of glycosaminoglycans (GAGs). Progressive accumulation of GAGs results in multi-organ dysfunction and a wide range of skeletal abnormalities. Standard treatments are not fully curative. For this reason, we have recently developed a hematopoietic stem cell-gene therapy approach for MPSIH patients which shows extensive metabolic correction and initial clinical response at the skeletal level. Other LSDs, including MPSIVA, MPSIVB and alpha-mannosidosis, are characterized by progressive accumulation of toxic GAGs resulting in typical skeletal manifestations. The pathogenetic mechanisms of the skeletal damage in these diseases are not completely understood and there is limited knowledge of bone correction mechanisms after gene therapy. The aims of this project are: i) to understand the pathophysiological mechanisms of skeletal damage in LSDs with skeletal involvement, with a specific focus for MPSIH, MPSIVA, MPSIVB and alpha-mannosidosis; ii) to investigate the mechanisms of cross-correction at the skeletal level after gene therapy in the same diseases. This will be obtained through the development of a technological platform to mimic the skeletal tissue and through the characterization of patient’s skeletal cellular players involved in bone remodelling.