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

Abstract

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 in mucopolysaccharidosis type I (MPS IH; Hurler syndrome), a lysosomal storage disorder caused by deficiency of α-l-iduronidase. MPS IH is characterized by a broad spectrum of clinical manifestations, including severe progressive skeletal abnormalities. Although BMT increases the life span of patients with MPS IH, musculoskeletal manifestations are only minimally responsive if the timing of BMT delays, suggesting already irreversible bone damage. In this study, we tested 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, we observed 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. We conclude that BMT at a very early stage in life markedly reduces signs and symptoms of MPS I before they appear.

• Authors: Alice Pievani, Isabella Azario, Laura Antolini, Tsutomu Shimada, Pravin Patel, Cristina Remoli, Benedetta Rambaldi, Maria Grazia Valsecchi, Mara Riminucci, Andrea Biondi, Shunji Tomatsu, Marta Serafini
• Journal: Blood (Blood) Vol. 125 Issue 10 Pg. 1662-71 (Mar 05 2015) ISSN: 1528-0020 [Electronic] United States
• PMID: 25298037 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society of Hematology.

Chemical References

• Glycosaminoglycans
• Iduronidase

Topics

• Age Factors
• Animals
• Animals, Newborn
• Bone Diseases, Developmental (metabolism, pathology, prevention & control)
• Bone Marrow Transplantation (methods)
• Bone and Bones (metabolism, pathology)
• Disease Models, Animal
• Female
• Glycosaminoglycans (blood, metabolism)
• Humans
• Iduronidase (genetics, metabolism)
• Infant, Newborn
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mucopolysaccharidosis I (genetics, pathology, therapy)