Methyl Donating artificial organelles to support liver cells in Non-alcoholic fatty liver disease

Description du projet

Des organites artificiels pour le traitement des stéatoses hépatiques non alcooliques

La stéatose hépatique non alcoolique (ou SHNA) est caractérisée au niveau cellulaire par diverses carences enzymatiques, notamment une biosynthèse réduite de la S-Adénosylméthionine (SAMe). C’est pourquoi le maintien de l’activité de l’enzyme synthétase SAMe a été proposé comme traitement potentiel des maladies du foie telles que la SHNA. Le projet MetD-AO, financé par l’UE, s’intéresse au développement d’organites artificiels pour remplacer l’activité biocatalytique de la SAMe synthétase manquante ou perdue dans les hépatocytes. La composition de ces organites artificiels facilite l’échappement lysosomal et assure une activité enzymatique réussie, dépassant ainsi les limitations antérieures. Les résultats obtenus devraient ouvrir la voie à des traitements innovants pour les maladies du foie.

Objectif

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world, encompassing a spectrum of liver damage. Multiple issues are involved on the cellular level in failing liver often including enzyme deficiencies such as reduced biosynthesis of S-adenosylmethionine (SAMe). Preserving SAMe homeostasis has only recently started to be considered as a potential therapeutic target in liver-related medical conditions. However, employing the required enzyme, SAMe synthetase (SAMe-synth), as a pharmaceutical, is challenging due to the general issues involved in intact (functional) protein delivery.
The aim of the MetD-AO project is to assemble organic SAMe-synth activity mimicking polymer nanoparticles as artificial organelles (AO) and their in vitro characterization of intracellular function in hepatocytes. AOs are typically nano-sized single compartment reactors, aimed to perform a specific encapsulated biocatalytic reaction within a cell to substitute for missing or lost function. The AO will be based on amphiphilic copolymers consisting of a methyl-donating unit, cholesterol methacrylate and poly(5-carboxypentyl acrylate) as membranolytic hydrophilic tail. The latter two will aim at facilitating self-assembly and lysosomal escape, respectively. To allow structurally intact AO to escape the lysosome is unique since typically, the carrier is destroyed and only the therapeutic cargo is release into the cytosol. The proposed AOs with methyl-donating ability are highly advanced because the few prior reported AOs with intracellular activity all considered reactive oxygen related aspects at best. The successful outcome of MetD-AO has the potential to open up entirely new therapeutic opportunities in NAFLD.
The complementary expertise of my host Dr. Stadler and me, a trained polymer chemist, will ensure a successful conduction of MetD-AO while it will enhance my future career prospects gaining experience in colloidal science and cell biology.