High value of 64Cu as a tool to evaluate the restoration of physiological copper excretion after gene therapy in Wilson’s disease

Abstract

Wilson’s disease (WD) is an inherited disorder of copper metabolism associated with mutations in ATP7B gene. We have shown that the administration of an adeno-associated vector (AAV) encoding a mini version of human ATP7B (VTX-801) provides long-term correction of copper metabolism in a murine WD model. In preparation of a future clinical trial, we have evaluated by positron emission tomography (PET) the value of 64Cu biodistribution, excretion pattern, and blood kinetics as pharmacodynamic biomarkers of VTX-801 effects. Six-week-old WD mice were injected intravenously with increasing doses of VTX-801 and 3 weeks or 3 months later with [64Cu]CuCl2. Untreated WD and wild-type (WT) mice were included as controls. Control WD mice showed increased hepatic 64Cu retention, reduced fecal excretion of the radiotracer, and altered 64Cu blood kinetics (BK) compared with WT mice. VTX-801 treatment in WD mice resulted in a significant reduction of hepatic 64Cu accumulation, the restoration of fecal 64Cu excretion, and the correction of 64Cu BK. This study showed that VTX-801 restores physiological copper metabolism in WD mice, confirming the mechanism of action of VTX-801, and demonstrated the translational potential of [64Cu]CuCl2-PET to explore VTX-801 pharmacodynamics in a minimally invasive and sensitive manner in WD patients. Wilson’s disease (WD) is an inherited disorder of copper metabolism associated with mutations in ATP7B gene. We have shown that the administration of an adeno-associated vector (AAV) encoding a mini version of human ATP7B (VTX-801) provides long-term correction of copper metabolism in a murine WD model. In preparation of a future clinical trial, we have evaluated by positron emission tomography (PET) the value of 64Cu biodistribution, excretion pattern, and blood kinetics as pharmacodynamic biomarkers of VTX-801 effects. Six-week-old WD mice were injected intravenously with increasing doses of VTX-801 and 3 weeks or 3 months later with [64Cu]CuCl2. Untreated WD and wild-type (WT) mice were included as controls. Control WD mice showed increased hepatic 64Cu retention, reduced fecal excretion of the radiotracer, and altered 64Cu blood kinetics (BK) compared with WT mice. VTX-801 treatment in WD mice resulted in a significant reduction of hepatic 64Cu accumulation, the restoration of fecal 64Cu excretion, and the correction of 64Cu BK. This study showed that VTX-801 restores physiological copper metabolism in WD mice, confirming the mechanism of action of VTX-801, and demonstrated the translational potential of [64Cu]CuCl2-PET to explore VTX-801 pharmacodynamics in a minimally invasive and sensitive manner in WD patients. IntroductionWilson’s disease (WD) is a rare autosomal recessive, debilitating, and life-threatening disorder of copper homeostasis that affects approximately one in 30,000 individuals, with wide geographical variations.1Członkowska A. Litwin T. Dusek P. Ferenci P. Lutsenko S. Medici V. Rybakowski J.K. Weiss K.H. Schilsky M.L. Wilson disease.Nat. Rev. Dis. Primers. 2018; 4: 21https://doi.org/10.1038/s41572-018-0018-3Crossref PubMed Scopus (254) Google Scholar In WD, mutations of the copper transporter ATP7B lead to decreased biliary copper excretion and a reduction in circulating holoceruloplasmin levels.1Członkowska A. Litwin T. Dusek P. Ferenci P. Lutsenko S. Medici V. Rybakowski J.K. Weiss K.H. Schilsky M.L. Wilson disease.Nat. Rev. Dis. Primers. 2018; 4: 21https://doi.org/10.1038/s41572-018-0018-3Crossref PubMed Scopus (254) Google Scholar, 2Saroli Palumbo C. Schilsky M.L. Clinical practice guidelines in Wilson disease.Ann. Transl. Med. 2019; 7: S65https://doi.org/10.21037/atm.2018.12.53Crossref PubMed Google Scholar, 3Ferenci P. Diagnosis of Wilson disease.Handb. Clin. Neurol. 2017; 142: 171-180https://doi.org/10.1016/B978-0-444-63625-6.00014-8Crossref PubMed Scopus (39) Google Scholar As a result, toxic levels of copper accumulate, primarily in the liver but also in the central nervous system; left untreated, WD is considered uniformly fatal. Current medical WD management includes copper chelators and/or zinc salt treatment, together with low-copper diet.2Saroli Palumbo C. Schilsky M.L. Clinical practice guidelines in Wilson disease.Ann. Transl. Med. 2019; 7: S65https://doi.org/10.21037/atm.2018.12.53Crossref PubMed Google Scholar, 3Ferenci P. Diagnosis of Wilson disease.Handb. Clin. Neurol. 2017; 142: 171-180https://doi.org/10.1016/B978-0-444-63625-6.00014-8Crossref PubMed Scopus (39) Google Scholar, 4European Association for Study of LiverEASL clinical practice guidelines: wilson’s disease.J. Hepatol. 2012; 56: 671-685https://doi.org/10.1016/j.jhep.2011.11.007Abstract Full Text Full Text PDF PubMed Scopus (709) Google Scholar, 5Roberts E.A. Schilsky M.L. American Association for Study of Liver Diseases (AASLD)Diagnosis and treatment of Wilson disease: an update.Hepatology. 2008; 47: 2089-2111https://doi.org/10.1002/hep.22261Crossref PubMed Scopus (910) Google Scholar Despite recognized benefits, current life-long management options have important limitations, including poor compliance, incomplete resolution of symptoms, and various side effects, among them severe and often not fully reversible neurological deterioration.2Saroli Palumbo C. Schilsky M.L. Clinical practice guidelines in Wilson disease.Ann. Transl. Med. 2019; 7: S65https://doi.org/10.21037/atm.2018.12.53Crossref PubMed Google Scholar,3Ferenci P. Diagnosis of Wilson disease.Handb. Clin. Neurol. 2017; 142: 171-180https://doi.org/10.1016/B978-0-444-63625-6.00014-8Crossref PubMed Scopus (39) Google Scholar As of today, liver transplantation, together with life-long immunosuppression, remains the only therapeutic option that can permanently restore physiological copper metabolism and is mostly limited to patients with acute liver failure or end-stage liver disease.2Saroli Palumbo C. Schilsky M.L. Clinical practice guidelines in Wilson disease.Ann. Transl. Med. 2019; 7: S65https://doi.org/10.21037/atm.2018.12.53Crossref PubMed Google Scholar, 3Ferenci P. Diagnosis of Wilson disease.Handb. Clin. Neurol. 2017; 142: 171-180https://doi.org/10.1016/B978-0-444-63625-6.00014-8Crossref PubMed Scopus (39) Google Scholar, 4European Association for Study of LiverEASL clinical practice guidelines: wilson’s disease.J. Hepatol. 2012; 56: 671-685https://doi.org/10.1016/j.jhep.2011.11.007Abstract Full Text Full Text PDF PubMed Scopus (709) Google Scholar, 5Roberts E.A. Schilsky M.L. American Association for Study of Liver Diseases (AASLD)Diagnosis and treatment of Wilson disease: an update.Hepatology. 2008; 47: 2089-2111https://doi.org/10.1002/hep.22261Crossref PubMed Scopus (910) Google Scholar However, recent data suggest the potential for added benefit of liver transplantation to newly diagnosed neurological WD patients unresponsive to medical treatment.6Poujois A. Sobesky R. Meissner W.G. Brunet A.S. Broussolle E. Laurencin C. Lion-François L. Guillaud O. Lachaux A. Maillot F. et al.Liver transplantation as a rescue therapy for severe neurologic forms of Wilson disease.Neurology. 2020; 94: e2189-e2202https://doi.org/10.1212/WNL.0000000000009474Crossref PubMed Scopus (21) Google ScholarLiver-directed adeno-associated vector (AAV)-based gene therapy has been recently shown to offer a non-surgical, permanent correction of copper metabolism in WD mice.7Murillo O. Luqui D.M. Gazquez C. Martinez-Espartosa D. Navarro-Blasco I. Monreal J.I. Guembe L. Moreno-Cermeño A. Corrales F.J. Prieto J. et al.Long-term metabolic correction of Wilson’s disease in a murine model by gene therapy.J. Hepatol. 2016; 64: 419-426https://doi.org/10.1016/j.jhep.2015.09.014Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 8Murillo O. Moreno D. Gazquez C. Barberia M. Cenzano I. Navarro I. Uriarte I. Sebastian V. Arruebo M. Ferrer V. et al.Liver of a gene in long-term restoration of copper homeostasis in a Wilson disease model in 2019; PubMed Scopus Google Scholar, D. O. Gazquez C. R. R. R. of the therapeutic of a gene correction in Wilson’s disease by Hepatol. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar administration of VTX-801, a an the of a to WD mice resulted in the reduction of copper in liver and restoration of fecal copper excretion, and of and levels in O. Moreno D. Gazquez C. Barberia M. Cenzano I. Navarro I. Uriarte I. Sebastian V. Arruebo M. Ferrer V. et al.Liver of a gene in long-term restoration of copper homeostasis in a Wilson disease model in 2019; PubMed Scopus Google D. O. Gazquez C. R. R. R. of the therapeutic of a gene correction in Wilson’s disease by Hepatol. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar therapeutic demonstrated for with liver and increased O. Moreno D. Gazquez C. Barberia M. Cenzano I. Navarro I. Uriarte I. Sebastian V. Arruebo M. Ferrer V. et al.Liver of a gene in long-term restoration of copper homeostasis in a Wilson disease model in 2019; PubMed Scopus Google of a clinical trial, we have the of a to the restoration of physiological copper metabolism in patients. in the showed copper metabolism fecal excretion and in WD patients copper including of in an in Wilson’s Med. PubMed Scopus Google Scholar, with copper and in to the of Wilson’s PubMed Scopus Google Scholar, S. P. M. L. of the of Wilson’s disease.J. Med. Google Scholar WD of the 64Cu administration showed by and I. in liver Med. PubMed Google Scholar recently by et A. M. A. L. Litwin T. of the copper in the of Wilson 2018; PubMed Scopus Google we have the and excretion and of VTX-801 treatment in a murine model of WD to in for of copper metabolism with positron emission tomography (PET) In the of 64Cu in and in a copper and of of in and WT for the of copper we the of in and WT and mice were and in showed a of the in blood by a in WT and and a in mice of in blood for WT for and for for WT and WT data with data in I. in liver Med. PubMed Google Scholar the were in metabolic and were for and the of in the of in were and WT or mice. fecal excretion of in WT and mice, the in mice. levels of 64Cu excretion were in mice the in to but were excretion, levels were and in and significant were among showed the levels blood kinetics (BK) and fecal excretion, but not excretion, biomarkers to copper by in and 64Cu in WT and showed the of in liver as as in the In a in the liver but in the of the liver value the in showed a hepatic of in in to WT and mice were and the in and As with in liver of mice in to of WT and mice. levels were in and in mice in to WT or and of 64Cu by and in and mice weeks of and 64Cu and of the with a of as of the liver were to of the by data is data of data were as the by administration to mice physiological and mice intravenously doses of and to to one shown to restore copper metabolism and in O. Moreno D. Gazquez C. Barberia M. Cenzano I. Navarro I. Uriarte I. Sebastian V. Arruebo M. Ferrer V. et al.Liver of a gene in long-term restoration of copper homeostasis in a Wilson disease model in 2019; PubMed Scopus Google Scholar weeks an of were and As we WT and mice and In VTX-801 treatment the of the in WD mice. doses of VTX-801 showed an in the 64Cu by also for with of and in WD and were the kinetics in blood and and in and of the by and in and weeks of and WT mice data the shown in and were and were and 64Cu and of the 64Cu kinetics of 64Cu in blood to have been of 64Cu in the is fecal excretion of 64Cu is 64Cu administration data of data were as the by of in also a to VTX-801 and that gene therapy and the of ATP7B restores physiological excretion of copper the biliary and fecal by and As for mice, in the liver and in the in with the of VTX-801, the of in the as in WT 64Cu in a reduction of in liver for WD mice with of 64Cu in and of mice were in WT VTX-801 treatment the resulted in a significant of 64Cu in and VTX-801 restoration of fecal excretion of and in WD mice were with of doses and of VTX-801 and 3 months later an of [64Cu]CuCl2. were as of WT and WD of weeks that weeks of In WT mice, levels to and increased to In WD mice, an of the by a in in WT of in in WT and in WD mice mice with the doses of VTX-801 and showed a to that in WT mice. levels in blood or a not as to that in mice in blood increased in a manner with of and treatment with and kinetics in blood and of and mice weeks of were and were and 64Cu of 64Cu in blood to is of 64Cu in the is fecal excretion of 64Cu is data were as the by were for 3 and the of as WD with VTX-801 showed a for levels of copper in with that the of VTX-801 levels not WT of excretion significant among the levels in WT were that in WD mice and WD with the of VTX-801 showed the levels of in liver of mice. VTX-801 treatment a reduction of 64Cu in the liver as as a of in the also by of in liver and 64Cu and or were In WT were a reduction of in liver In mice of the in the WD mice with VTX-801 showed a reduction of 64Cu in liver as as a reduction in the or in to WD and of 64Cu by and in and mice weeks of and and 64Cu the of the the liver were to of hepatic of 64Cu and and and of and hepatic data is data of data were as the by in and VTX-801 reduction in hepatic 64Cu increased in and doses of vector levels to WT significant levels of were in the of in that were reduced by VTX-801 treatment is a model of WD, and of gene the and in WD including liver and of biliary of of the model to the therapeutic of gene therapy a with disease and of the to as a in J. Lutsenko S. S. S. C. of the murine ATP7B gene in copper and hepatic PubMed Scopus Google Scholar We demonstrated that an vector an to restore copper metabolism and physiological copper excretion in WD mice in a and O. Moreno D. Gazquez C. Barberia M. Cenzano I. Navarro I. Uriarte I. Sebastian V. Arruebo M. Ferrer V. et al.Liver of a gene in long-term restoration of copper homeostasis in a Wilson disease model in 2019; PubMed Scopus Google Scholar and in of a future clinical we the of a and minimally invasive to the of gene therapy in copper metabolism in WD is a that that for therapeutic and In of is as a and to the of O. M. E. C. A. J. et for a to 2020; PubMed Scopus Google S. F. S. of and 2020; Scopus Google Scholar of or by a sensitive and for and A. V. J. A. M. F. et in patients with 2020; 4: PubMed Google Scholar, E. J. M. D. S. P. D. J. et as a for 2018; PubMed Scopus Google Scholar, et of in patients with Med. 2018; PubMed Scopus Google Scholar clinical is have been associated with the of the doses the has been to explore the copper metabolism in and WD as a for WD and as a sensitive to copper by the fecal copper excretion, and of copper of in an in Wilson’s Med. PubMed Scopus Google Scholar, with copper and in to the of Wilson’s PubMed Scopus Google Scholar, S. P. M. L. of the of Wilson’s disease.J. Med. Google Scholar, I. in liver Med. PubMed Google Scholar In the of has been shown to WD and WT T. S. I. hepatic copper in emission PubMed Scopus Google Scholar, F. Lutsenko S. O. emission tomography of copper metabolism in the model of Wilson’s 2012; PubMed Scopus Google Scholar, F. Lutsenko S. O. copper metabolism in model of Wilson’s disease with and 2012; PubMed Scopus Google Scholar and I. in liver Med. PubMed Google Scholar the or 64Cu of in the as an of copper that ATP7B This has been recently by et A. M. A. L. Litwin T. of the copper in the of Wilson 2018; PubMed Scopus Google Scholar confirming the of the In we that the by in to WT WD weeks of the administration of VTX-801 in WD mice in a However, weeks of we a WD mice a reduction of in WD an a of 64Cu in and levels that were of WT In WT the of in is to the In WD, to the of not we have shown in WD with disease and of liver O. Luqui D.M. Gazquez C. Martinez-Espartosa D. Navarro-Blasco I. Monreal J.I. Guembe L. Moreno-Cermeño A. Corrales F.J. Prieto J. et al.Long-term metabolic correction of Wilson’s disease in a murine model by gene therapy.J. Hepatol. 2016; 64: 419-426https://doi.org/10.1016/j.jhep.2015.09.014Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar In we demonstrated that the of liver in WD mice by the administration of an resulted in an in in in WD mice, is as an acute as has been also shown in WD patients acute liver C. O. J. for acute liver failure to Wilson PubMed Scopus Google Scholar VTX-801 administration blood in WD mice. the of VTX-801, has a the reduction of hepatic retention, we a significant in the in to WD mice, is to the one shown by WD mice. This by the that doses of VTX-801 of liver in WD mice but not to the levels of in O. Luqui D.M. Gazquez C. Martinez-Espartosa D. Navarro-Blasco I. Monreal J.I. Guembe L. Moreno-Cermeño A. Corrales F.J. Prieto J. et al.Long-term metabolic correction of Wilson’s disease in a murine model by gene therapy.J. Hepatol. 2016; 64: 419-426https://doi.org/10.1016/j.jhep.2015.09.014Abstract Full Text Full Text PDF PubMed Scopus (75) Google O. Moreno D. Gazquez C. Barberia M. Cenzano I. Navarro I. Uriarte I. Sebastian V. Arruebo M. Ferrer V. et al.Liver of a gene in long-term restoration of copper homeostasis in a Wilson disease model in 2019; PubMed Scopus Google Scholar the administration of VTX-801 doses in a manner in the of in to acute biomarkers to a to the of VTX-801 the restoration of levels in in we to the of WD mice to of the injected in the liver and showed a for biliary copper excretion as by and of in were in patients and WD T. S. I. hepatic copper in emission PubMed Scopus Google Scholar, F. Lutsenko S. O. emission tomography of copper metabolism in the model of Wilson’s 2012; PubMed Scopus Google Scholar, F. Lutsenko S. O. copper metabolism in model of Wilson’s disease with and 2012; PubMed Scopus Google K.H. S. P. and copper and in by 2020; PubMed Scopus Google Scholar, wilson’s disease the of 2020; PubMed Scopus Google Scholar, R. S. Schilsky M.L. S. with for of biliary copper excretion in model of Wilson disease.J. Med. 2012; PubMed Scopus Google Scholar In WT of copper is the biliary and fecal in WD mice, copper is in the liver and the is to restore an with as toxic copper levels in primarily in the VTX-801 administration reduced hepatic and increased biliary and fecal excretion in a manner and weeks of the of VTX-801, associated with copper metabolism and excretion were to WT in mice, copper is the levels WT VTX-801 we a reduction in in the of However, the of in the of WD and WT significant but a to levels in WD in is to we were and can by the in liver of WD et D. K.H. S. P. of human copper metabolism and of Wilson disease by positron emission 2019; PubMed Google Scholar showed a of the and tomography diagnosed WD patients with we have to the of VTX-801 treatment liver in mice the value in WT and in WD mice, that the liver in WT and and in WD mice VTX-801 reduced in a in with et D. K.H. S. P. of human copper metabolism and of Wilson disease by positron emission 2019; PubMed Google Scholar and suggest that of value for WD is also an to the pharmacodynamics of a the restoration of physiological copper However, that D. K.H. S. P. of human copper metabolism and of Wilson disease by positron emission 2019; PubMed Google Scholar to or that of and with copper and in to the of Wilson’s PubMed Scopus Google Scholar showed hepatic in WD patients in and the of et and and to the of the patients with WD limited is in the recent study by et the patients by copper or in and the patients WD biodistribution, we levels in the and of WD mice of WT and weeks of As to the in the to the of the in the VTX-801 treatment, we a to the levels in in a In the of the a in WD to the neurological of the with by et F. Lutsenko S. O. emission tomography of copper metabolism in the model of Wilson’s 2012; PubMed Scopus Google Scholar, F. O. F. of copper metabolism in model of Wilson’s disease by Dis. 2017; PubMed Scopus Google Scholar and et F. Lutsenko S. O. emission tomography of copper metabolism in the model of Wilson’s 2012; PubMed Scopus Google Scholar, F. O. F. of copper metabolism in model of Wilson’s disease by Dis. 2017; PubMed Scopus Google Scholar levels of in the of WD in in to WT However, et showed that in that showed in the of WD mice in WT F. O. F. of copper metabolism in model of Wilson’s disease by Dis. 2017; PubMed Scopus Google Scholar in of to VTX-801 in the of WD that is of but that also to the mechanism is the levels of in the of weeks of but not levels were reduced in mice, the of with the of in the blood for WD patients administration of copper chelators and or zinc chelators by copper excretion, zinc by copper E.A. Schilsky M.L. American Association for Study of Liver Diseases (AASLD)Diagnosis and treatment of Wilson disease: an update.Hepatology. 2008; 47: 2089-2111https://doi.org/10.1002/hep.22261Crossref PubMed Scopus (910) Google Scholar As to VTX-801, of medical restore fecal and the of a to the pharmacodynamic of VTX-801 in patients or and and were to an for evaluated and by the of for and by the of of the WD model and mice were by with WT were in in an a with to and were injected with intravenously the and an and to in a of the the mice were in metabolic by a therapeutic a version of the human ATP7B gene the of the has been O. Moreno D. Gazquez C. Barberia M. Cenzano I. Navarro I. Uriarte I. Sebastian V. Arruebo M. Ferrer V. et al.Liver of a gene in long-term restoration of copper homeostasis in a Wilson disease model in 2019; PubMed Scopus Google Scholar of the vector preparation shown in the as by the and were and a were and injected of blood the of and data were in the as the to and were metabolic and data were as the the of and were in a with an and of of and and a resolution of and mice were the with in to a the were in a with a the with and a of and were the the were and the were in the the liver to a a of of the to a that the liver with as the of the the kinetics of the we the the liver and and and were as a were and to with a as of the with the were for the and the and the of is a to that the as and were for by the by the IntroductionWilson’s disease (WD) is a rare autosomal recessive, debilitating, and life-threatening disorder of copper homeostasis that affects approximately one in 30,000 individuals, with wide geographical variations.1Członkowska A. Litwin T. Dusek P. Ferenci P. Lutsenko S. Medici V. Rybakowski J.K. Weiss K.H. Schilsky M.L. Wilson disease.Nat. Rev. Dis. Primers. 2018; 4: 21https://doi.org/10.1038/s41572-018-0018-3Crossref PubMed Scopus (254) Google Scholar In WD, mutations of the copper transporter ATP7B lead to decreased biliary copper excretion and a reduction in circulating holoceruloplasmin levels.1Członkowska A. Litwin T. Dusek P. Ferenci P. Lutsenko S. Medici V. Rybakowski J.K. Weiss K.H. Schilsky M.L. Wilson disease.Nat. Rev. Dis. Primers. 2018; 4: 21https://doi.org/10.1038/s41572-018-0018-3Crossref PubMed Scopus (254) Google Scholar, 2Saroli Palumbo C. Schilsky M.L. Clinical practice guidelines in Wilson disease.Ann. Transl. Med. 2019; 7: S65https://doi.org/10.21037/atm.2018.12.53Crossref PubMed Google Scholar, 3Ferenci P. Diagnosis of Wilson disease.Handb. Clin. Neurol. 2017; 142: 171-180https://doi.org/10.1016/B978-0-444-63625-6.00014-8Crossref PubMed Scopus (39) Google Scholar As a result, toxic levels of copper accumulate, primarily in the liver but also in the central nervous system; left untreated, WD is considered uniformly fatal. Current medical WD management includes copper chelators and/or zinc salt treatment, together with low-copper diet.2Saroli Palumbo C. Schilsky M.L. Clinical practice guidelines in Wilson disease.Ann. Transl. Med. 2019; 7: S65https://doi.org/10.21037/atm.2018.12.53Crossref PubMed Google Scholar, 3Ferenci P. Diagnosis of Wilson disease.Handb. Clin. Neurol. 2017; 142: 171-180https://doi.org/10.1016/B978-0-444-63625-6.00014-8Crossref PubMed Scopus (39) Google Scholar, 4European Association for Study of LiverEASL clinical practice guidelines: wilson’s disease.J. Hepatol. 2012; 56: 671-685https://doi.org/10.1016/j.jhep.2011.11.007Abstract Full Text Full Text PDF PubMed Scopus (709) Google Scholar, 5Roberts E.A. Schilsky M.L. American Association for Study of Liver Diseases (AASLD)Diagnosis and treatment of Wilson disease: an update.Hepatology. 2008; 47: 2089-2111https://doi.org/10.1002/hep.22261Crossref PubMed Scopus (910) Google Scholar Despite recognized benefits, current life-long management options have important limitations, including poor compliance, incomplete resolution of symptoms, and various side effects, among them severe and often not fully reversible neurological deterioration.2Saroli Palumbo C. Schilsky M.L. Clinical practice guidelines in Wilson disease.Ann. Transl. Med. 2019; 7: S65https://doi.org/10.21037/atm.2018.12.53Crossref PubMed Google Scholar,3Ferenci P. Diagnosis of Wilson disease.Handb. Clin. Neurol. 2017; 142: 171-180https://doi.org/10.1016/B978-0-444-63625-6.00014-8Crossref PubMed Scopus (39) Google Scholar As of today, liver transplantation, together with life-long immunosuppression, remains the only therapeutic option that can permanently restore physiological copper metabolism and is mostly limited to patients with acute liver failure or end-stage liver disease.2Saroli Palumbo C. Schilsky M.L. Clinical practice guidelines in Wilson disease.Ann. Transl. Med. 2019; 7: S65https://doi.org/10.21037/atm.2018.12.53Crossref PubMed Google Scholar, 3Ferenci P. Diagnosis of Wilson disease.Handb. Clin. Neurol. 2017; 142: 171-180https://doi.org/10.1016/B978-0-444-63625-6.00014-8Crossref PubMed Scopus (39) Google Scholar, 4European Association for Study of LiverEASL clinical practice guidelines: wilson’s disease.J. Hepatol. 2012; 56: 671-685https://doi.org/10.1016/j.jhep.2011.11.007Abstract Full Text Full Text PDF PubMed Scopus (709) Google Scholar, 5Roberts E.A. Schilsky M.L. American Association for Study of Liver Diseases (AASLD)Diagnosis and treatment of Wilson disease: an update.Hepatology. 2008; 47: 2089-2111https://doi.org/10.1002/hep.22261Crossref PubMed Scopus (910) Google Scholar However, recent data suggest the potential for added benefit of liver transplantation to newly diagnosed neurological WD patients unresponsive to medical treatment.6Poujois A. Sobesky R. Meissner W.G. Brunet A.S. Broussolle E. Laurencin C. Lion-François L. Guillaud O. Lachaux A. Maillot F. et al.Liver transplantation as a rescue therapy for severe neurologic forms of Wilson disease.Neurology. 2020; 94: e2189-e2202https://doi.org/10.1212/WNL.0000000000009474Crossref PubMed Scopus (21) Google ScholarLiver-directed adeno-associated vector (AAV)-based gene therapy has been recently shown to offer a non-surgical, permanent correction of copper metabolism in WD mice.7Murillo O. Luqui D.M. Gazquez C. Martinez-Espartosa D. Navarro-Blasco I. Monreal J.I. Guembe L. Moreno-Cermeño A. Corrales F.J. Prieto J. et al.Long-term metabolic correction of Wilson’s disease in a murine model by gene therapy.J. Hepatol. 2016; 64: 419-426https://doi.org/10.1016/j.jhep.2015.09.014Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 8Murillo O. Moreno D. Gazquez C. Barberia M. Cenzano I. Navarro I. Uriarte I. Sebastian V. Arruebo M. Ferrer V. et al.Liver of a gene in long-term restoration of copper homeostasis in a Wilson disease model in 2019; PubMed Scopus Google Scholar, D. O. Gazquez C. R. R. R. of the therapeutic of a gene correction in Wilson’s disease by Hepatol. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar administration of VTX-801, a an the of a to WD mice resulted in the reduction of copper in liver and restoration of fecal copper excretion, and of and levels in O. Moreno D. Gazquez C. Barberia M. Cenzano I. Navarro I. Uriarte I. Sebastian V. Arruebo M. Ferrer V. et al.Liver of a gene in long-term restoration of copper homeostasis in a Wilson disease model in 2019; PubMed Scopus Google D. O. Gazquez C. R. R. R. of the therapeutic of a gene correction in Wilson’s disease by Hepatol. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar therapeutic demonstrated for with liver and increased O. Moreno D. Gazquez C. Barberia M. Cenzano I. Navarro I. Uriarte I. Sebastian V. Arruebo M. Ferrer V. et al.Liver of a gene in long-term restoration of copper homeostasis in a Wilson disease model in 2019; PubMed Scopus Google of a clinical trial, we have the of a to the restoration of physiological copper metabolism in patients. in the showed copper metabolism fecal excretion and in WD patients copper including of in an in Wilson’s Med. PubMed Scopus Google Scholar, with copper and in to the of Wilson’s PubMed Scopus Google Scholar, S. P. M. L. of the of Wilson’s disease.J. Med. Google Scholar WD of the 64Cu administration showed by and I. in liver Med. PubMed Google Scholar recently by et A. M. A. L. Litwin T. of the copper in the of Wilson 2018; PubMed Scopus Google we have the and excretion and of VTX-801 treatment in a murine model of WD to in for of copper metabolism with positron emission tomography (PET) In the of 64Cu in and in a copper and of

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