The New England Journal of Medicine ( NEJM ) has published a paper showing that inactivating mutations of the angiopoeitin-like 4 ( ANGPTL4 ) gene are associated with a significantly reduced risk of coronary artery disease ( CAD ) in humans.
ANGPTL4 inhibits lipoprotein lipase ( LPL ), an enzyme that helps break down triglycerides, a form of fat derived from food.
Previous studies have found that activation of LPL leads to the reduction of circulating triglycerides, increased levels of which are thought to be an independent risk factor for ischemic cardiovascular disease. It was hypothesized, therefore, that genetic mutations inactivating ANGPTL4 would lead to activation of LPL, low levels of circulating triglycerides and reduced risk of cardiovascular disease.
In this study, researchers at the RGC ( Regeneron Genetics Center ) sequenced the exomes of individuals in the DiscovEHR cohort, comprised of de-identified Geisinger Health System patients who consented to participate in the MyCode Community Health Initiative.
Analyses revealed that individuals with one or two copies of the p.E40K mutation, which was previously known to inactivate ANGPTL4, had about 19% lower CAD risk.
People with one of 13 other ANGPTL4 loss-of-function mutations newly-identified by the researchers had an almost 45% reduction in CAD risk.
This paper has also demonstrated the advantages of the combination of technologies. Using VelociGene technology, researchers developed animal models that corroborated the human genetics findings. The VelocImmune platform was leveraged to create a fully human monoclonal antibody inhibitor of ANGPTL4 that reduced triglyceride levels in mice and non-human primates.
Further evaluation is needed to characterize the potential efficacy and safety of ANGPTL4 inhibition in humans.
Regeneron currently has an angiopoeitin-like 3 ( ANGPTL3 ) antibody, known as Evinacumab or REGN1500, in clinical development.
ANGPTL4 and ANGPTL3 are thought to be related inhibitors of LPL.
Source: Regeneron Pharmaceuticals, 2016