Although clinical trials of HDL-boosting CETP inhibitors have so far failed to produce positive results, many other avenues of HDL-related research remain active. A glimpse at the very early phases of two intriguing lines of research in this area was offered on Monday at the AHA.
Apo A-1 is thought to be the key HDL component that removes cholesterol from cells. Almost a decade ago a study demonstrating regression of atherosclerosis with apo A-1 Milano caused tremendous excitement, but the recombinant product has not yet undergone further research or commercial development. A somewhat similar approach is now being developed by by CSL Limited with a novel formulation of human apo A-1, known as CSL112. At the AHA, Andreas Gille and colleagues reported giving CSL112 to healthy volunteers and observing dramatic increases in the ability of the HDL in their blood plasma to remove cholesterol from cells.
Gille reported that the increase in cholesterol efflux capacity was higher and occurred faster than any previous therapy, more than doubling within two hours, as opposed to a 2.9% increase after 4 weeks with niacin or 6.8% after 24 months with dalcetrapib. “CSL112 may offer a novel means to rapidly remove cholesterol from plaque following a heart attack,” said Gille. To date two phase 1 studies have demonstrated a favorable safety profile, he reported. A phase 2 study of CSL112 in patients with an acute coronary syndrome is planned.
An even more unusual approach is being explored by Alan Fogelman and his team, who have genetically engineered a tomato to produce a small peptide, 6F, that mimics the action of apo A-1. They then fed the tomatoes to mice with high LDL levels. After consuming the tomatoes along with a high-fat and high-calorie diet, there were a number of signs suggesting a beneficial effect, including significantly lower levels of inflammation, higher levels of the antioxidant paraoxonase, higher HDL levels, and less atherosclerotic plaque.
“To our knowledge this is the first example of a drug with these properties that has been produced in an edible plant and is biologically active when fed without any isolation or purification of the drug,” Fogelman said in an AHA press release.
Here are the two press releases from the AHA:
Infusing ‘good’ cholesterol protein may lower risk of subsequent heart attack
- In early tests in humans, infusing the chief protein in “good” cholesterol rapidly boosted the body’s ability to move cholesterol out of plaque-clogged arteries.
- If the approach succeeds in clinical trials, it could reduce the high risk of an early subsequent heart attack compared to drugs that raise good cholesterol levels more slowly.
- Cholesterol extraction from cells rose immediately (up to 270 percent from baseline).
- PreBeta1-HDL, a subfraction of HDL involved in cholesterol elimination, increased dramatically (up to 3,600 percent from baseline).
Genetically engineered tomatoes decrease plaque build-up in mice
- For the first time, researchers have genetically engineered tomato plants to produce a peptide that mimics the actions of good cholesterol when eaten.
- Mice that ate the freeze-dried, ground tomatoes had less inflammation and reduced plaque build-up in their arteries.
- lower blood levels of inflammation;
- higher paraoxonase activity, an anti-oxidant enzyme associated with good cholesterol and related to a lower risk of heart disease;
- higher levels of good cholesterol;
- decreased lysophosphatidic acid, a tumor promoter that accelerates plaque build-up in arteries in animal models; and
- less atherosclerotic plaque.