Gene therapy of Wilson disease: A "golden" opportunity using rAAV on the 50th anniversary of the discovery of the virus.

Wilson disease (WD) was a once progressive and uniformly fatal inherited disorder of copper metabolism. Medical therapy to arrest progression or prevent complications of WD was developed in the 1950s with the introduction of parenterally administered BAL [1], and over the next two decades by oral therapy with d-penicillamine, trientine, and zinc [2]. Effective therapy for WD requires life-long administration of daily medication. At least 30–50% of patients on medication for WD have periods of nonadherence, some suffering liver failure, others developing potentially irreversible neurologic or psychiatric symptoms. Herein lies the justification for developing therapies that would provide correction instead of serial treatment of WD. Liver transplantation (LT) is curative for WD. Biliary copper excretion is restored, ceruloplasmin and copper levels in the circulation normalize, neurologic and psychiatric disease stabilizes or improves and Kayser Fleischer rings disappear over time [2]. Following LT, patients do not require WD-specific therapy, but rather life-long immunosuppression. Thus LT proved that the defect for WD lay within the liver, consistent with physiologic studies showing reduced biliary copper excretion in WD patients [3]. Therefore targeting the liver to correct the defect in biliary copper excretion would provide a cure for WD. The WD gene was identified as the trans-membrane copper transporter ATP7B in 1993, and studies showed that the ATP7B protein was preferentially expressed in hepatocytes [6]. ATP7B facilitates copper transport into bile and incorporation of copper into ceruloplasmin. Animal models of WD, the LEC rat and the toxic milk mouse, lack ATP7B and manifest hepatic copper accumulation due to impaired biliary copper excretion and low circulating ceruloplasmin levels [4]. Atp7b knockout mice develop the same phenotype. Therefore, introduction of ATP7B into hepatocytes should correct the phenotype. Proof of principle for gene therapy came from the expression of ATP7B in the liver of LEC rats and murine models of WD using adenoviral and lentiviral