Wilson’s disease (WD) is a disorder of copper metabolism that can present with hepatic, neurologic, or psychiatric disturbances, or a combination of these. If untreated WD is a life-threatening condition. Recently, we have demonstrated that an adeno-associated vector (AAV) serotype Anc80 carrying a reduced version of human ATP7B cDNA (VTX-801) provides long-term correction of copper metabolism in young male and female WD mice. Here, we challenge the therapeutic efficacy of VTX-801 treating animals with advanced-stage WD. To this end, 12-, 16- and 20-week-old WD mice received a dose of VTX-801 identified as therapeutic in young animals. To evaluate the therapeutic effectiveness of the vector, a 6 month follow-up of mice was conducted and biomarkers of disease status including urinary copper excretion rate and biochemical and copper-related parameters in serum were monitored. In addition, copper content was measured in liver, kidney and brain tissue, liver histology was analysed and vector genome copies and transgene expression in liver were quantified. VTX-801 prevented the progression of WD and improved most pathological features regardless of the age at treatment administration. Nonetheless, some disease biomarkers such as serum levels of transaminase and bile acids and some features of liver histology and fibrosis were not completely corrected. Lower transduction efficiency associated with disease progression was observed, which could explain these results.
Based on these data, we can conclude that, although VTX-801 therapy is safe and efficient even at advanced-stage WD, lower therapeutic efficacy is observed when vector administration is performed in mice with advanced liver damage.