title: Long-term metabolic correction of Wilson's disease in a murine model by gene therapy.
abstract: OBJECTIVE
  Wilson's disease (WD) is an autosomal recessively inherited copper storage disorder due to mutations in the ATP7B gene that causes hepatic and neurologic symptoms. Current treatments are based on lifelong copper chelating drugs and zinc salts, which may cause side effects and do not restore normal copper metabolism. In this work we assessed the efficacy of gene therapy to treat this condition.
  
  
  METHODS
  We transduced the liver of the Atp7b(-/-) WD mouse model with an adeno-associated vector serotype 8 (AAV8) encoding the human ATP7B cDNA placed under the control of the liver-specific α1-antitrypsin promoter (AAV8-AAT-ATP7B). After vector administration we carried out periodic evaluation of parameters associated with copper metabolism and disease progression. The animals were sacrificed 6months after treatment to analyze copper storage and hepatic histology.
  
  
  RESULTS
  We observed a dose-dependent therapeutic effect of AAV8-AAT-ATP7B manifested by the reduction of serum transaminases and urinary copper excretion, normalization of serum holoceruloplasmin, and restoration of physiological biliary copper excretion in response to copper overload. The liver of treated animals showed normalization of copper content and absence of histological alterations.
  
  
  CONCLUSIONS
  Our data demonstrate that AAV8-AAT-ATP7B-mediated gene therapy provides long-term correction of copper metabolism in a clinically relevant animal model of WD providing support for future translational studies.
authors.affiliation: Gene Therapy and Regulation of Gene Expression Program, CIMA, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain; IDISNA, Instituto de Investigacion Sanitaria de Navarra, Spain.
authors.forename: Oihana
authors.initials: O
authors.lastname: Murillo
authors.affiliation: Gene Therapy and Regulation of Gene Expression Program, CIMA, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain; IDISNA, Instituto de Investigacion Sanitaria de Navarra, Spain.
authors.forename: Daniel Moreno
authors.initials: DM
authors.lastname: Luqui
authors.affiliation: Gene Therapy and Regulation of Gene Expression Program, CIMA, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain; IDISNA, Instituto de Investigacion Sanitaria de Navarra, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Gazquez
authors.affiliation: IDISNA, Instituto de Investigacion Sanitaria de Navarra, Spain; Clinical Chemistry Department, University Clinic of Navarra, University of Navarra, Pamplona, Spain.
authors.forename: Debora
authors.initials: D
authors.lastname: Martinez-Espartosa
authors.affiliation: IDISNA, Instituto de Investigacion Sanitaria de Navarra, Spain; Department of Chemistry and Soil Sciences, University of Navarra, Pamplona, Spain.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Navarro-Blasco
authors.affiliation: IDISNA, Instituto de Investigacion Sanitaria de Navarra, Spain; Clinical Chemistry Department, University Clinic of Navarra, University of Navarra, Pamplona, Spain.
authors.forename: Jose Ignacio
authors.initials: JI
authors.lastname: Monreal
authors.affiliation: IDISNA, Instituto de Investigacion Sanitaria de Navarra, Spain; Department of Morphology, CIMA, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Guembe
authors.affiliation: IDISNA, Instituto de Investigacion Sanitaria de Navarra, Spain; Hepatology Program, CIMA, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Armando
authors.initials: A
authors.lastname: Moreno-Cermeño
authors.affiliation: IDISNA, Instituto de Investigacion Sanitaria de Navarra, Spain; Hepatology Program, CIMA, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain; CIBERehd, University of Navarra, Pamplona, Spain.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Corrales
authors.affiliation: Gene Therapy and Regulation of Gene Expression Program, CIMA, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain; IDISNA, Instituto de Investigacion Sanitaria de Navarra, Spain; Hepatology Program, CIMA, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Prieto
authors.affiliation: Gene Therapy and Regulation of Gene Expression Program, CIMA, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain; IDISNA, Instituto de Investigacion Sanitaria de Navarra, Spain.
authors.forename: Ruben
authors.initials: R
authors.lastname: Hernandez-Alcoceba
authors.affiliation: Gene Therapy and Regulation of Gene Expression Program, CIMA, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain; IDISNA, Instituto de Investigacion Sanitaria de Navarra, Spain. Electronic address: ggasegui@unav.es.
authors.forename: Gloria
authors.initials: G
authors.lastname: Gonzalez-Aseguinolaza
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics; D003300:Copper / Q000378:metabolism*; D000073840:Copper-Transporting ATPases; D004195:Disease Models, Animal; D018450:Disease Progression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006527:Hepatolenticular Degeneration / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010446:Peptide Fragments / Q000235:genetics; D016896:Treatment Outcome; D000515:alpha 1-Antitrypsin / Q000235:genetics
chemical_list: C486201:Atp7a protein, mouse; C508153:C105Y peptide; D027682:Cation Transport Proteins; D010446:Peptide Fragments; D000515:alpha 1-Antitrypsin; D003300:Copper; D000251:Adenosine Triphosphatases; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases
keywords: ATPase copper transporting beta polypeptide (ATP7B); Adenoassociated virus (AAV); Copper metabolism; Gene transfer