CARDIOPHAGY · Tissue-specific induction of autophagy as an innovative therapeutic strategy in cardiovascular and metabolic disease.

Tissue-specific induction of autophagy as an innovative therapeutic strategy in cardiovascular and metabolic disease.

The Western diet, high in fat and sugar, is driving a surge in cardiovascular diseases (CVDs) like atherosclerosis (AS). AS involves the build-up of plaques made mostly of cholesterol on artery walls, which harden and narrow the arteries, restricting blood flow. This can lead to severe health issues such as heart attacks and strokes. CVDs are the leading cause of death globally, responsible for approximately 17.9 million deaths annually, according to the WHO. In Europe, CVDs affect nearly 49 million people, costing €210 billion each year. The Western diet is also linked to a rise in metabolic disorders like Metabolic Associated Steatohepatitis Liver Disease (MASLD), formerly known as Non-Alcoholic Fatty Liver Disease (NAFLD). MASLD involves the accumulation of fat in the liver and is prevalent in 24% of the European population, with numbers expected to rise due to increasing obesity and diabetes rates. MASLD can progress to a more severe form, Non-Alcoholic Steatohepatitis (NASH), leading to liver cirrhosis and cancer. MASLD also contributes to AS, making it a major health concern. Currently, the only treatment options for AS and MASLD are lifestyle changes, such as reducing calorie intake and increasing physical activity. These changes stimulate autophagy, a natural process where cells remove and recycle damaged components, which is beneficial for both CVDs and metabolic disorders. Autophagy plays a crucial role in maintaining vascular health, and its impairment is linked to the progression of AS. Inducing autophagy pharmacologically has shown promise in delaying plaque progression and stabilizing plaques in preclinical studies. Despite the potential of autophagy-inducing compounds, their development as drugs is challenging due to side effects and toxicity when used systemically. Our project aims to overcome these challenges by developing targeted autophagy inducers that only activate autophagy in specific cells involved in AS and MASLD, minimizing side effects and increasing drug development potential. For AS, we plan to attach autophagy inducers to 'homing peptides' that specifically target dysfunctional endothelial cells in atherosclerotic plaques. For MASLD, we will link autophagy inducers to a molecule that directs them to the liver, using its high affinity for liver-specific receptors. The project's goals are: 1. Design and synthesis of cell-targeted autophagy inducers for endothelial and liver cells. 2. Evaluation of these compounds' autophagy-inducing effects, toxicity, and pharmacokinetics in cell models of atherosclerosis and hepatocyte cells. 3. In vivo testing in mouse models to establish proof of concept for organ-targeted autophagy induction in AS and MASLD. This research aims to develop innovative therapeutics for AS and MASLD, enhancing treatment options and improving patient outcomes.

Data: CORDIS, © European Union