Cardiovascular disease (CVD) is the number one cause of morbidity and mortality in the western world. Despite low HDL cholesterol being the most commonly observed risk factor in coronary artery disease, there is still no prescribed medicine currently on the market that reliably and significantly raises HDL as its primary mechanism of cardiovascular prevention. Epidemiological data suggests that relatively small increases in HDL levels can have a large cardio-protective effect, even when LDL cholesterol levels are high.

Xenon applied its clinical genetic approach and worldwide networks to search for single gene disorders with extreme HDL phenotypes. We identified a rare recessive disorder called Tangier disease. The cardinal features for this disorder, are an almost complete absence of plasma HDL caused by a defect in cholesterol efflux. We discovered that the ABCA1 transporter was the gene responsible for Tangier disease. Furthermore, we showed that mutations in ABCA1 were causal for a related disorder familial hypoalphalipoproteinemia, a disease associated with markedly reduced HDL-cholesterol levels and premature cardiovascular disease.

To treat low HDL, we would need to up regulate ABCA1 thereby increasing cholesterol efflux leading to an increase in plasma HDL levels and a reduction in risk of developing CVD. We demonstrated that up-regulation of ABCA1 is protective in humans. We identified humans with a gain-of-function mutation that increased HDL levels leading to a markedly reduced risk of CVD. In addition, a transgenic mouse was created which replicated the normal tissue distribution of ABCA1 and increased the protein levels several fold. These mice had increased plasma HDL levels and showed protection against atherosclerosis in gold standard models.

The goal of Xenon’s ABCA1 program is to develop small molecule drugs that increase the activity of ABCA1.