Identifying and characterising new targets, drugs, and small molecules for prevention and treatment of coronary artery disease

Bakgrund:

Coronary artery disease (CAD) results from the progression of atherosclerosis in the coronary vessels and is the main cause of death in Sweden and worldwide. Novel treatment strategies for the primary and secondary prevention of CAD are needed, in part because existing LDL-lowering drugs leave residual risk and likely even increase the risk of diabetes.

Genome-wide association studies identified hundreds of genetic loci that are robustly associated with CAD and/or its risk factors. However, the genes and mechanisms through which most loci act remain uncharacterised. Målsättning:

The objective of this project is to identify targets that can be translated into efficient therapeutics for prevention and treatment of CAD without adverse side effects. The specific aims are to: 1) characterise the role of 50 candidate genes in CAD-related traits; 2) examine if putative causal genes represent promising targets; 3) examine if drugs exist against those targets and explore if they can be repurposed; and 4) identify and scrutinise small molecules targeting promising targets not yet acted on by existing drugs.

Arbetsplan:

My group developed and validated high-throughput, image-based model systems for dyslipidaemia, early-stage atherosclerosis, diabetes, and cardiac rate and rhythm in zebrafish larvae. Zebrafish orthologues of the 50 most promising candidate genes in genetic loci for coronary artery disease will be targeted using CRISPR/Cas9 and examined for a role in CAD-related traits using high-throughput, in vivo imaging.

For putative causal genes, we will explore possible side effects using a phenome-wide association study in UK Biobank data, as well as using additional characterisation in zebrafish. Next, we will examine if drugs against promising targets exist, and if so, if they can be repurposed, using data from Swedish registries and characterisation in zebrafish.

Finally, small molecules anticipated to engage with targets not yet acted on by existing drugs will be scrutinised in zebrafish. Betydelse:

Repurposing of existing drugs for other indications would imply the quickest and safest way to the clinic. In addition, this research program will increase our understanding of CAD pathophysiology, and likely yield small molecules that can be taken forward on the path towards clinical trials.