1:Vivet therapeutics; 2:Center for Applied Medical Research; 3:Gene Therapy, FIMA, CIMA Universidad de Navarra, IdisNA, Pamplona, Spain.; 4:Department of Nuclear Medicine, Clinica Universidad de Navarra, IdisNA, Pamplona, Spain.; 5:Translational Molecular Imaging Unit, University of Navarra, Pamplona, Spain,; 6:Vivet Therapeutics, Paris, France.

Wilson’s disease (WD) is an inherited disorder of copper metabolism associated with mutations in ATP7B gene. We have shown that the administration of an adeno-associated vector (AAV) encoding a mini version of human ATP7B (VTX-801) provides long-term correction of copper metabolism in a murine WD model. In preparation of a future clinical trial, we have evaluated by Positron Emission Tomography (PET) the value of 64Cu biodistribution, excretion pattern and blood kinetics as pharmacodynamic biomarkers of VTX-801 effects. Six-week-old WD mice were injected intravenously with increasing doses of VTX-801 and three weeks or 3 months later with [64Cu]CuCl₂. Untreated WD and Wild type (Wt) mice were included as controls. Control WD mice showed increased hepatic 64Cu retention, reduced faecal excretion of the radiotracer and altered 64Cu blood kinetics (BK) compared to Wt mice. VTX-801 treatment in WD mice resulted in a significant reduction of hepatic 64Cu accumulation, the restoration of faecal 64Cu excretion and the correction of 64Cu blood kinetics (BK). This study showed that VTX-801 restores physiological copper metabolism in WD mice, confirming the mechanism of action of VTX-801, and demonstrated the translational potential of [64Cu]CuCl₂-PET to explore VTX-801 pharmacodynamics in a minimally invasive and sensitive manner in WD patients.