702. Long Term Metabolic Correction of Wilson Disease

Abstract

Wilson disease (WD) is an autosomal recessively inherited copper storage disorder due to mutations in the ATP7B gene resulting in impaired biliary copper excretion and hepatic copper accumulation. The increased hepatic copper concentration causes hepatocellular injury of variable intensity from acute liver failure to chronic hepatitis evolving to cirrhosis. Most often the first manifestation of the disorder is the hepatic disease which may be followed by copper deposition in the brain with resulting neurological damage. Current treatments are based on copper chelators that promote urinary excretion of the metal. These therapies should be maintained lifelong, 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. We transduced the liver of Atp7b-/- mice (a model of WD) with an adeno-associated vector serotype 8 (AAV8) encoding the human ATP7B cDNA placed under the control of the liver-specific a1-antitripsin promoter. After vector administration we performed serial determinations of serum transaminases, serum holoceruloplasmin concentration and ferroxidase activity and urinary copper excretion. In addition we assessed liver cooper concentration, oxidative status of hepatic proteins and histological liver damage in samples obtained at 6 months after therapy. We observed a dose-dependent therapeutic effect manifested by the reduction of transaminasemia and urinary copper excretion and normalization of serum holoceruloplasmin. Furthermore, we documented complete reversal of all hepatic alterations, including copper content, histopathological changes and protein oxidation. Conclusion: our data demonstrate that gene therapy provides long term correction of WD in a clinically relevant animal model of this disorder.