Oihana Murillo1, Daniel Moreno Luqui1, Cristina Gazquez1, Debora Martinez-Espartosa2, Iñigo Navarro-Blasco3, Jose Ignacio Monreal2, Laura Guembe4, Armando Moreno-Cermeño5, Fernando J Corrales6, Jesus Prieto7, Ruben Hernandez-Alcoceba1, Gloria Gonzalez-Aseguinolaza8. 1. 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. 2. IDISNA, Instituto de Investigacion Sanitaria de Navarra, Spain; Clinical Chemistry Department, University Clinic of Navarra, University of Navarra, Pamplona, Spain. 3. IDISNA, Instituto de Investigacion Sanitaria de Navarra, Spain; Department of Chemistry and Soil Sciences, University of Navarra, Pamplona, Spain. 4. IDISNA, Instituto de Investigacion Sanitaria de Navarra, Spain; Department of Morphology, CIMA, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain. 5. IDISNA, Instituto de Investigacion Sanitaria de Navarra, Spain; Hepatology Program, CIMA, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain. 6. 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. 7. 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. 8. 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.
Abstract
BACKGROUND & AIMS: 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.
BACKGROUND & AIMS: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(-/-) WDmouse model with an adeno-associated vector serotype 8 (AAV8) encoding the humanATP7B 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: Josef Lichtmannegger; Christin Leitzinger; Ralf Wimmer; Sabine Schmitt; Sabine Schulz; Yaschar Kabiri; Carola Eberhagen; Tamara Rieder; Dirk Janik; Frauke Neff; Beate K Straub; Peter Schirmacher; Alan A DiSpirito; Nathan Bandow; Bipin S Baral; Andrew Flatley; Elisabeth Kremmer; Gerald Denk; Florian P Reiter; Simon Hohenester; Friedericke Eckardt-Schupp; Norbert A Dencher; Jerzy Adamski; Vanessa Sauer; Christoph Niemietz; Hartmut H J Schmidt; Uta Merle; Daniel Nils Gotthardt; Guido Kroemer; Karl Heinz Weiss; Hans Zischka Journal: J Clin Invest Date: 2016-06-20 Impact factor: 14.808
Authors: Maria Cristina Ballesteros-Briones; Eva Martisova; Erkuden Casales; Noelia Silva-Pilipich; Maria Buñuales; Javier Galindo; Uxua Mancheño; Marta Gorraiz; Juan J Lasarte; Grazyna Kochan; David Escors; Alfonso R Sanchez-Paulete; Ignacio Melero; Jesus Prieto; Ruben Hernandez-Alcoceba; Sandra Hervas-Stubbs; Cristian Smerdou Journal: Mol Ther Date: 2019-09-16 Impact factor: 11.454