title: 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.affiliation: Dulbecco Telethon Institute, Centro Ricerca M. Tettamanti, Department of Pediatrics, and.
authors.forename: Alice
authors.initials: A
authors.lastname: Pievani
authors.affiliation: Dulbecco Telethon Institute, Centro Ricerca M. Tettamanti, Department of Pediatrics, and.
authors.forename: Isabella
authors.initials: I
authors.lastname: Azario
authors.affiliation: Centro di Biostatistica per l'epidemiologia clinica, Department of Health Sciences, University of Milano-Bicocca, Monza, Italy;
authors.forename: Laura
authors.initials: L
authors.lastname: Antolini
authors.affiliation: Department of Biomedical Research, Alfred I. duPont Institute Hospital for Children, Wilmington, DE;
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Shimada
authors.affiliation: Department of Biomedical Research, Alfred I. duPont Institute Hospital for Children, Wilmington, DE;
authors.forename: Pravin
authors.initials: P
authors.lastname: Patel
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy; and.
authors.forename: Cristina
authors.initials: C
authors.lastname: Remoli
authors.affiliation: Centro Ricerca M. Tettamanti, Department of Pediatrics, and.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Rambaldi
authors.affiliation: Centro di Biostatistica per l'epidemiologia clinica, Department of Health Sciences, University of Milano-Bicocca, Monza, Italy;
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Valsecchi
authors.affiliation: Department of Molecular Medicine, Sapienza University, Rome, Italy; and.
authors.forename: Mara
authors.initials: M
authors.lastname: Riminucci
authors.affiliation: Centro Ricerca M. Tettamanti, Department of Pediatrics, and Department of Pediatrics, University of Milano-Bicocca, San Gerardo Hospital/Fondazione Monza e Brianza per il Bambino e la sua Mamma, Monza, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Biondi
authors.affiliation: Department of Biomedical Research, Alfred I. duPont Institute Hospital for Children, Wilmington, DE;
authors.forename: Shunji
authors.initials: S
authors.lastname: Tomatsu
authors.affiliation: Dulbecco Telethon Institute, Centro Ricerca M. Tettamanti, Department of Pediatrics, and.
authors.forename: Marta
authors.identifier: http://orcid.org/0000-0001-8105-6476
authors.initials: M
authors.lastname: Serafini
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001848:Bone Diseases, Developmental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016026:Bone Marrow Transplantation / Q000379:methods*; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006025:Glycosaminoglycans / Q000097:blood / Q000378:metabolism; D006801:Humans; D007068:Iduronidase / Q000235:genetics / Q000378:metabolism; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008059:Mucopolysaccharidosis I / Q000235:genetics / Q000473:pathology* / Q000628:therapy*
chemical_list: D006025:Glycosaminoglycans; D007068:Iduronidase