Project description
Artificial organelles for the treatment of non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD) is characterised at the cellular level by various enzyme deficiencies including reduced biosynthesis of S-Adenosylmethionine (SAMe). Therefore, maintaining the activity of the SAMe synthetase enzyme has been proposed as a potential treatment for liver diseases such as NAFLD. The EU-funded MetD-AO project is proposing the development of artificial organelles to substitute for missing or lost SAMe synthetase biocatalytic activity in hepatocytes. The composition of these artificial organelles facilitates lysosomal escape and ensures successful enzyme activity, overcoming previous limitations. Results are expected to pave the way for innovative treatments for liver diseases.
Objective
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.
Fields of science
Programme(s)
Funding Scheme
MSCA-IF-EF-ST - Standard EFCoordinator
8000 Aarhus C
Denmark