Neonatal bone marrow transplantation prevents bone pathology in a mouse model of mucopolysaccharidosis type I

Neonatal bone marrow transplantation (BMT) could offer a novel therapeutic opportunity for genetic disorders by providing sustainable levels of the missing protein at birth, thus preventing tissue damage. We tested this concept inmucopolysaccharidosis type I (MPS IH; Hurler syndrome), a lysosomal storage disorder caused by deficiency of a-L-iduronidase. MPS IH is characterized by a broad spectrum of clinicalmanifestations, including severe progressive skeletal abnormalities. AlthoughBMTincreases the life spanofpatientswithMPSIH, musculoskeletal manifestations are only minimally responsive if the timing of BMT delays, suggesting already irreversible bonedamage. In this study,wetested the hypothesis that transplanting normal BM into newborn MPS I mice soon after birth can prevent skeletal dysplasia. We observed that neonatal BMT was effective at restoring α-L-iduronidase activity and clearing elevated glycosaminoglycans in blood and multiple organs. At 37 weeks of age,weobserved an almost complete normalization of all bone tissue parameters, using radiographic, microcomputed tomography, biochemical, and histological analyses. Overall, the magnitude of improvements correlated with the extent of hematopoietic engraftment. Weconclude that BMT at a very early stage in lifemarkedly reduces signs and symptoms of MPS I before they appear.