The mainstay of therapy for Wilson disease is pharmacologic treatment with chelating agents such as D-Penicillamine (DPA) and Trientine. Chelating agents result in urinary copper elimination but do not restore copper metabolism. Recently, we have demonstrated that an adeno-associated vector (AAV) serotype Anc80 carrying a reduced version of the human ATP7B cDNA (VTX-801) provides long-term correction of copper metabolism in young male and female WD mice. Nonetheless, lower therapeutic efficacy is observed when VTX-801 is administered to WD mice with advanced liver damage. Here, we tested whether a pre-treatment with DPA prevented advanced-stage WD development and allowed for greater therapeutic benefit from gene therapy in aged WD mice. For this purpose, WD mice were treated with DPA from weaning and at 20 weeks of age, when untreated WD mice usually present advanced liver damage, they received a therapeutic dose of VTX-801. To evaluate the therapeutic effectiveness of this combination therapy, a 6 month follow-up was conducted and biomarkers of disease status were monitored. Our results show that at 20 weeks of age, liver function tests of DPA-treated mice were comparable to those of healthy controls and that VTX-801 administration to DPA-treated animals provided full correction of copper metabolism. In summary, this study demonstrates that DPA halts the development of liver disease in WD mice, thus favoring more effective gene therapy at 20 weeks of age. All in all, these results demonstrate the usefulness of combining both therapies for the treatment of Wilson's disease.