title: Neonatal bone marrow transplantation prevents liver disease in a murine model of erythropoietic protoporphyria.
abstract: OBJECTIVE
  Erythropoietic protoporphyria (EPP) is an inherited disorder of heme biosynthesis caused by partial ferrochelatase deficiency, resulting in protoporphyrin IX (PPIX) accumulation in erythrocytes, responsible for skin photosensitivity. In some EPP patients, the development of cholestatic liver injury due to PPIX accumulation can lead to hepatic failure. In adult EPP mice, bone marrow transplantation (BMT) leads to skin photosensitivity correction but fails to reverse liver damages, probably because of the irreversible nature of liver fibrosis. Our aim was to determine the time course of liver disease progression in EPP mice and to evaluate the protective effect of BMT into neonates.
  
  
  METHODS
  We studied the development of liver disease from birth in EPP mice, in relation with erythroid and hepatic PPIX accumulation. To prevent the development of liver disease, BMT was performed into newborn mice using a novel busulfan-mediated preconditioning assay.
  
  
  RESULTS
  We showed that hepatic PPIX accumulates during the first 2 weeks and correlates with the onset of a progressive liver fibrosis in 12-day-old EPP mice. Transplantation of normal congenic hematopoietic stem cells into EPP neonates led to long-term donor hematopoiesis recovery. A full correction of erythroid PPIX accumulation and skin photosensitivity was obtained. Furthermore, five months after neonatal BMT, liver damage was almost completely prevented.
  
  
  CONCLUSIONS
  We demonstrated for the first time that BMT could be successfully used to prevent liver disease in EPP mice and suggested that BMT would be an attractive therapeutic option to prevent severe liver dysfunction in EPP patients.
authors.affiliation: Univ. de Bordeaux Biothérapies des maladies génétiques et cancers, U1035, F-33000 Bordeaux, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Duchartre
authors.forename: Nicolas
authors.initials: N
authors.lastname: Petit
authors.forename: Corrine
authors.initials: C
authors.lastname: Moya
authors.forename: Magalie
authors.initials: M
authors.lastname: Lalanne
authors.forename: Pierre
authors.initials: P
authors.lastname: Dubus
authors.forename: Hubert de
authors.initials: Hd
authors.lastname: Verneuil
authors.forename: François
authors.initials: F
authors.lastname: Moreau-Gaudry
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Richard
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016026:Bone Marrow Transplantation; D002066:Busulfan / Q000008:administration & dosage; D004195:Disease Models, Animal; D018450:Disease Progression; D005294:Ferrochelatase / Q000235:genetics; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017093:Liver Failure / Q000517:prevention & control; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019653:Myeloablative Agonists / Q000008:administration & dosage; D046351:Protoporphyria, Erythropoietic / Q000150:complications* / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D011524:Protoporphyrins / Q000378:metabolism; D019172:Transplantation Conditioning
chemical_list: D019653:Myeloablative Agonists; D011524:Protoporphyrins; C028025:protoporphyrin IX; D005294:Ferrochelatase; D002066:Busulfan