A trio of papers from a UCSD group has found a connection between oxidized lipids and inflammation in atherosclerosis, osteoporosis and ischemia injury, breathing new life into the once popular “oxidation hypothesis” of atherosclerosis.
The authors are spinning out Oxitope Inc. to develop a mAb that selectively targets oxidized forms of lipids.
The oxidation hypothesis, first put forward in 1983 by Michael Brown and Joseph Goldstein, argues that reactive oxygen species (ROS) are the primary drivers of heart disease.
It was based on observations that both activated immune cells and oxidized phospholipids on LDL are the earliest, most reliable markers of atherosclerotic plaques in humans. In addition, preclinical studies had shown that oxidized, but not non-oxidized, forms of lipoproteins are capable of inducing immune cell activation.
However, a string of failed or underwhelming trials in the 1990s and 2000s testing dietary antioxidants such as vitamin E and β-carotene caused the hypothesis to fall out of favor.
According to Joseph Witztum, who led the new atherosclerosis work, those studies were started prematurely, without solid preclinical evidence of efficacy. For example, he said vitamin E “was never shown to effectively prevent atherosclerosis” in animal models, and molecular modeling experiments suggest the supplement may work in the wrong direction by promoting free radical formation.
He argues the oxidation hypothesis has never been properly tested in the clinic or in animal models. The statins and anti-PCSK9 mAbs marketed for atherosclerosis do not constitute direct tests of the hypothesis, he said, as they work by decreasing levels of non-oxidized, rather than oxidized, LDL in blood.
Witztum, who is a professor of medicine at the University of California San Diego and an Oxitope co-founder, thought a naturally occurring mouse antibody, E06, discovered two decades ago in his lab, could serve as