Title of project

Liver-targeted AMPK modulation in fatty-liver disease

Abstract

The earth is now harboring more individuals living with obesity than with underweight, accelerating the progression of several non-communicable co-morbidities. Particularly, the expansion of intrahepatic fat depots in metabolic dysfunction-associated steatotic liver disease (MASLD) poses a risk for the progression to the inflammatory and severe state, i.e. metabolic dysfunction-associated steatohepatitis (MASH). The heterogeneous etiology of MASH has rendered it defiant to most monotherapeutic approaches. This is evident from the clinical data of the first FDA-approved therapy for the treatment of MASH, Resmetirom, which only provides symptomatic relief in ~25% of patients in clinical trials. Complex diseases like these, with diverse underlying causes, have historically been resistant to single-drug therapies. However, combination therapies have shown promise in overcoming these challenges, particularly in the treatment of obesity, where there has been significant progress with single-molecule multi-agonists. Although extending the dual-agonist strategy to MASLD treatment seems logical, it is notable that more than 90% of MASLD drug candidates in clinical trials still focus on monotherapy. To address this gap, we propose developing a first-in-class, multimodal unimolecular drug specifically designed to treat fatty liver disease. In the research group of Christoffer Clemmensen, we have pioneered a strategy that uses peptide hormones to target small-molecule drugs toward specific tissues. Building on this platform, we propose to combine a potent AMP-activated protein kinase (AMPK) activator with a pharmacokinetically optimized glucagon receptor agonist. This approach synergistically harnesses the lipid metabolism benefits of both components while minimizing their individual side effects. This PhD project aims to demonstrate the target specificity and efficacy of this new drug candidate in vivo, evaluate its safety and effectiveness in mouse models of MASH, and advance its preclinical development. We will also investigate cardiovascular safety, pharmacokinetics, and biodistribution, laying the foundation for potential commercialization and ventures into spinout creation.