Evaluation of efficacy and safety of AAV8-ΔC4ATP7B gene therapy in a mutant mouse model of Wilson's disease.

Wilson's disease (WD) is an autosomal recessive disorder caused by pathogenic variants in the gene, resulting in the toxic accumulation of copper (Cu). Impaired Cu homeostasis in WD is characterized by low serum ceruloplasmin, excess hepatic Cu, and elevated urinary Cu. WD often presents with hepatic and/or neurological diseases and is fatal if untreated. Adeno-associated virus (AAV)-mediated gene therapy holds promise for WD, but challenges remain in efficacy and safety. Here, we established an R780L knockin (KI) mouse model corresponding to the human R778L variant and investigated the therapeutic efficacy and safety of liver-targeted AAV8-mediated (AAV8-ΔC4ATP7B) gene therapy in this model. The results demonstrated the mice recapitulated key features of impaired Cu metabolism in WD but had mild liver disease. Ten-week-old mice received a single-dose of AAV8-ΔC4ATP7B and were sacrificed at 8 or 30 weeks after treatment. Treated mice showed normalization of serum ceruloplasmin, reduced hepatic Cu, decreased urinary Cu, and reversed liver histopathology. Serum transaminases had a transient increase at 8 weeks after treatment but returned to normal at 30 weeks after treatment. These data provide evidence for the efficacy and safety of AAV8-ΔC4ATP7B in animals, supporting clinical translation to patients with WD.