Long-term metabolic correction of Wilson’s disease in a murine model by gene therapy

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• 作者：Oihana Murillo¹ ; ² ; ^&dagger ; ; Daniel Moreno Luqui¹ ; ² ; ^&dagger ; ; Cristina Gazquez¹ ; ² ; Debora Martinez-Espartosa² ; ³ ; Iñ ; igo Navarro-Blasco² ; ⁷ ; Jose Ignacio Monreal² ; ³ ; Laura Guembe² ; ⁴ ; Armando Moreno-Cermeñ ; o² ; ⁵ ; Fernando J. Corrales² ; ⁵ ; ⁶ ; Jesus Prieto¹ ; ² ; ⁵ ; ^&Dagger ; ; Ruben Hernandez-Alcoceba¹ ; ² ; ^&Dagger ; ; Gloria Gonzalez-Aseguinolaza¹ ; ² ; ^&Dagger ; ; ^{ggasegui@unav.es" class="auth_mail" title="E-mail the corresponding author}
• 关键词：AAV ; Adenoassociated virus ; ATP7B ; ATPase copper transporting beta polypeptide ; TGN ; trans-Golgi network
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：64
• 期：2
• 页码：419-426
• 全文大小：1839 K

文摘

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 6 months 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.