Ricerc@Sapienza

Mucopolysaccharidosis type I (MPS-I), a lysosomal storage disorder caused by a deficiency of alpha-L-iduronidase enzyme, results in the progressive accumulation of glycosaminoglycans and consequent multiorgan dysfunction. Despite the effectiveness of hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) in correcting clinical manifestations related to visceral organs, complete improvement of musculoskeletal and neurocognitive defects remains an unmet challenge and provides an impact on patients' quality of life. We tested the therapeutic efficacy of combining HSCT and ERT in the neonatal period. Using a mouse model of MPS-I, we demonstrated that such combination therapy produced an improved effect on organs usually refractory to current treatment. Importantly, HSCT could prevent the production of anti-IDUA antibodies that may reduce ERT efficacy. Additive beneficial effects of combining both treatments were also observed on the reduction of skeletal anomalies. At the brain level, the combination therapy provided a moderate decrease of neuroinflammation and metabolic abnormalities. Our findings demonstrated that the combination of HSCT and ERT at neonatal age provides a further step forward in the treatment of MPS-I.