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Laura Gauthier

Innovative therapeutic strategies for Wilson's disease

Published on 15 November 2019
Thesis presented November 15, 2019

Wilson's disease is is a genetic disorder of copper metabolism. Mutations on atp7b gene, encoding for a copper ATPase, result in toxic copper accumulation mainly in the liver. Actual copper chelating therapies, using D-Penicillamine (Trolovol®) and triethylenetetramine (Trientine®), present many side effects resulting in poor compliance of the treatment.
Previously in the SyMMES laboratory, a copper chelator has been developed to specifically chelate the hepatic excess copper. This pro-drug, based on a bioinspired copper chelator Cu(I) specific, has been functionalized by N-acetyl-D-galactosamine (GalNAc) sugars to be specifically recognized by asialoglycoproteine receptors (ASGPr).
In this project, we propose an alternative strategy taking advantage of nanoparticles. Nanostructured Lipid Carriers (NLC) developed in the DTBS team (Lipidots®) were used as carrier for a lipophilic version of the copper chelator previously developed. The NLC's surface has been functionalized with GalNAc units to specifically target hepatic cells via ASGPR. The first part of this work focuses on NLC functionalization with GalNAc and its quantification using UPLC-ELSD system. Internalization of NLC has been evaluated by flow cytometry. Interaction between functionalized NLC and a lectin model were performed by SPR in collaboration with IBS. In the second part of this work, encapsulations of lipophilic versions of the copper chelator were quantified by HPLC coupled with SPE extraction. The ability of loaded NLC to deliver an efficient copper chelator has been evaluated on two different hepatic cell types (wild type and atp7b knock out) in collaboration with LCBM.

Wilson, copper, chelator, nanoparticles

On-line thesis.