High value of 64Cu as a tool to evaluate the restoration of physiological copper excretion after gene therapy in Wilson’s disease

Molecular Therapy: Methods & Clinical Development

Cristina Gazquez¹  Gloria Gonzalez-Aseguinolaza¹  Maria Collantes²  Bernard Bénichou²  Daniel Moreno³  Ruben Hernandez-Alcoceba³  Oihana Murillo³  Miren Barberia³  Margarita Ecay³  Blanche Tamarit⁴  Jean Philippe Combal⁵  Ivan Peñuelas⁵  Veronica Ferrer⁵  Anne Douar⁵ 

[1] Translational Molecular Imaging Unit, IdisNA, Clinica Universidad de Navarra, 31008 Pamplona, Spain;Department of Nuclear Medicine, IdisNA, Clinica Universidad de Navarra, 31008 Pamplona, Spain;Gene Therapy and Regulation of Gene Expression Program, Centro de Investigacion Medica Aplicada (CIMA), FIMA, Navarra Institute for Health Research (IdisNA), University of Navarra, Avda Pio XII 55, 31008 Pamplona, Spain;Translational Molecular Imaging Unit, IdisNA, Clinica Universidad de Navarra, 31008 Pamplona, Spain;Vivet Therapeutics SAS, Paris, France;

关键词: Wilson’s disease;    radiocopper;    AAV;    ATP7B;    copper metabolism;    gene transfer;   

DOI  :  

来源: DOAJ

【 摘 要 】

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 3 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 fecal excretion of the radiotracer, and altered 64Cu blood kinetics (BK) compared with WT mice. VTX-801 treatment in WD mice resulted in a significant reduction of hepatic 64Cu accumulation, the restoration of fecal 64Cu excretion, and the correction of 64Cu 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.

【 授权许可】

Unknown