Early Look: New Methods To Enhance Cholesterol Efflux Reply

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

Study Highlights:
  • 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.
American Heart Association Meeting Report
LOS ANGELES, November 5, 2012 — An intravenous infusion of good cholesterol could reduce the risk of a subsequent heart attack, researchers reported at the American Heart Association’s Scientific Sessions 2012.
In a small, early study, researchers noted that an intravenous infusion of the chief protein inhigh density lipoprotein External link (HDL or “good” cholesterol) seems to rapidly boost the body’s ability to move cholesterol out of plaque-clogged arteries External link.
In the days and weeks after a heart attack External link or chest pain, patients are at high risk of another attack. Standard heart attack medications, such as aspirin and anti-platelet drugs, prevent clotting but don’t help eliminate the underlying cause — cholesterol that has built up in artery plaque.
Other HDL drugs, such as niacin and fibrates, which do attack the underlying cause, gradually raise HDL and may prevent heart attacks years after the start of therapy.
The study involves CSL112, an infusible and natural human formulation of Apolipoprotein A-1 (ApoA-1), the key protein in HDL particles that transports cholesterol from arteries and other tissues into the liver for disposal.
“In a current multi-center study, CSL112 will be administered as a short series of weekly IV infusions initiated shortly following a heart attack or heart-related chest pain,” said Andreas Gille, M.D., Ph.D., lead author of the study and Head of Clinical and Translational Science Strategy at CSL Limited in Parkville, Australia. “Our aim is to address a significant gap in acute coronary syndrome management by reducing the high risk of early recurrent events.”
Researchers studied markers of cholesterol movement in response to a single infusion of CSL112 at doses ranging from 5 to 135 mg/kg in 57 healthy volunteers.
Compared with a placebo infusion, they found:
  • 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).
“Overall, CSL112 behaved as well or better than we expected and all the changes are consistent with the desired elevation in reverse cholesterol transport activity,” Gille said. “We did not observe any unfavorable changes in the low density lipoprotein or ‘bad’ cholesterol-related biomarkers tested.”
The safety and behavior of CSL112 in patients with stable heart disease is being evaluated in a multi-center trial.
Co-authors are Rachael Easton, M.D., Ph.D.; Samuel D. Wright, Ph.D.; and Charles L. Shear, Dr.P.H. Author disclosures are on the abstract.
CSL Limited funded the study.
Learn more about cholesterol at the American Heart Association’s Cholesterol Website External link.
Follow news from the American Heart Association’s Scientific Sessions 2012 via Twitter:@HeartNews External link
Statements and conclusions of study authors that are presented at American Heart Association scientific meetings are solely those of the study authors and do not necessarily reflect association policy or position.  The association makes no representation or warranty as to their accuracy or reliability. The association receives funding primarily from individuals; foundations and corporations (including pharmaceutical, device manufacturers and other companies) also make donations and fund specific association programs and events.  The association has strict policies to prevent these relationships from influencing the science content.  Revenues from pharmaceutical and device corporations are available atwww.heart.org/corporatefunding External link.
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Genetically engineered tomatoes decrease plaque build-up in mice

Study Highlights:
  • 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.
American Heart Association Meeting Report:
LOS ANGELES, Nov. 5, 2012 — For the first time, genetically engineered tomato plants produced a peptide that mimics the actions of good cholesterol when eaten, researchers reported at the American Heart Association’s Scientific Sessions 2012.
In the study, mice that ate the freeze-dried, ground tomatoes had less inflammation and reduced atherosclerosis External link (plaque build-up in the arteries).
“We have found a new and practical way to make a peptide that acts like the main protein in good cholesterol, but is many times more effective and can be delivered by eating the plant,” said Alan M. Fogelman, M.D., senior author of the study and executive chair of the Department of Medicine and director of the Atherosclerosis Research Unit in the David Geffen School of Medicine at UCLA.
Researchers genetically engineered the tomatoes to produce 6F, a small peptide that mimics the action of ApoA-1, the chief protein in high density lipoprotein External link (HDL or “good” cholesterol). They fed the tomatoes to mice that lack the ability to remove low density lipoprotein (LDL or “bad” cholesterol) from their blood and readily develop inflammation and atherosclerosis when consuming a high-fat diet.
After the mice ate the tomatoes as 2.2 percent of their Western-style high-fat, calorie-packed diet, those given the peptide-enhanced tomatoes had significantly:
  • 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.
“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.
Co-authors are Arnab Chattopadhyay, Ph.D.; Mohamad Navab, Ph.D.; Greg Hough, B.S.; David Meriwether, B.S.; Gao Feng, Ph.D.; Victor Grijalva, B.S.; James R. Springstead, Ph.D.; Mayakonda N. Palgunachari, Ph.D.; Ryan Namiri-Kalantari, B.S.; G.M. Anantharamaya, Ph.D.; Robin Farias-Eisner, M.D., Ph.D.; and Srinivasa T. Reddy, Ph.D. Author disclosures are on the abstract.
The National Heart, Lung, and Blood Institute funded the study.
Follow news from the American Heart Association Scientific Sessions 2012 via Twitter:@HeartNews External link.
Statements and conclusions of study authors that are presented at American Heart Association scientific meetings are solely those of the study authors and do not necessarily reflect association policy or position.  The association makes no representation or warranty as to their accuracy or reliability. The association receives funding primarily from individuals; foundations and corporations (including pharmaceutical, device manufacturers and other companies) also make donations and fund specific association programs and events.  The association has strict policies to prevent these relationships from influencing the science content.  Revenues from pharmaceutical and device corporations are available atwww.heart.org/corporatefunding External link.
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