The Heart Foundation supports a large and diverse research program devoted to unraveling the causes of heart disease at a genetic and molecular level, improving methods of early detection, and developing and testing new preventive and therapeutic strategies.
December 2011
By Prediman K. (P.K.) Shah, MD, FACC, FACP, FCCP
Shapell and Webb Family Endowed Chair in Cardiology
Director, Division of Cardiology and
Oppenheimer Atherosclerosis Research Center
Professor of Medicine, David Geffen School of Medicine at UCLA
Professor, Cedars-Sinai Professorial Series
The Heart Foundation supports specific research programs of the Division of Cardiology’s Oppenheimer Atherosclerosis Research Center, under the direction of Dr. PK Shah.
The Cedars-Sinai Division of Cardiology is internationally recognized for outstanding heart care built on decades of innovation and leading-edge research. From cardiac imaging and advanced diagnostics to surgical repair of complex heart problems, the training of future heart specialists, and leading-edge research that deepens medical knowledge and practice, the Cardiology Division is renowned for excellence and innovations.
The Oppenheimer Atherosclerosis Research Center (ARC) was established in 1993 by Dr. PK Shah. A team of 17 researchers work in the ARC under the overall direction of Dr. Shah to unravel the mechanisms leading to plaque build-up and develop new treatments for atherosclerosis, a common and lethal disease responsible for most heart attacks, strokes and sudden deaths.
Brief Update on a Selection of Key Research Projects Supported by The Heart Foundation
Over the past year, Dr. P.K. Shah, Director of the Division of Cardiology and the Oppenheimer Atherosclerosis Research Center (ARC), and his team have continued on their path to uncover the causes of arterial plaque build-up and to develop new treatments for the resulting condition called atherosclerosis. Fighting against cardiac disease since 1976, Dr. Shah has logged countless hours of study, clinical trials, and even serendipitous discovery to bring him closer to realizing his ultimate goal of eliminating atherosclerosis. Because of his strength in clinical work, as well as his expertise among researchers and talent as a mentor and guide, he is heralded as one of the top cardiologists in the country. His interests in the broader field of medicine—including neurology, neuroscience, and immunology—make him an excellent physician, capable of tackling complex illnesses that require a more holistic and integrated approach.
A number of interesting developments have been made over the past year. Of highest interest is the new vaccine against arterial plaque. There are two components to this vaccine: 1.) an active component, which stimulates the immune system to react against cholesterol and 2.) a passive component, which consists of a designer antibody against one of the antigens in the bad cholesterol. This antibody can be directly injected as an immunization. The antibody injection speeds up the body’s ability to directly react to the threat. The development of the passive vaccine is essentially a pre-form of the vaccine.
As a matter of demonstration, Dr. Shah and his team have shown in laboratory tests that with just three injections, given a week apart, plaque (in mice) was decreased by 50 percent by the designer antibody which forms the passive vaccine. In coordination with Swedish company BioInvent, who has partnered with Genentech, this antibody procedure has entered human clinical trials in the U.S. and Europe. Phase I, which measures safety, has been completed resulting in zero safety issues. Phase II is on-going in the U.S. to establish the proof of concept for the antibody. The goal is to rapidly shrink or stabilize existing plaque.
Dr. Shah has filed a request for permission from the Food & Drug Administration and is waiting for approval to launch human clinical trials of the active vaccine. If the vaccine works as well in humans as it does in mice, it may one day become part of a childhood vaccination program. The implications of this are far-reaching, and if it works, it would be a big jump beyond traditional treatment methods.
Two years ago, when Dr. Tomoyuki Honjo of Japan began work in Dr. Shah’s laboratory as a post-doctoral fellow, he and Dr. Shah’s colleague in the laboratory, Dr. Kunag-Yuh Chyu, started to follow an idea that tested if the vaccine described above would prevent aneurysm formation. Aneurysms are basically arteries that bulge in a localized fashion, like a balloon, and are at risk of rupturing or bursting. In the U.S., about 16,000 people die annually from ruptured aneurysms.
Dr. Honjo’s idea was based on the notion that if inflammation is one of the culprits in aneurysm formation and rupture and if the vaccine suppresses inflammation, then perhaps it would also have a favorable effect on aneurysm formation. A mouse model was used to test the theory, with the vaccine applied to one group while a second group served as the control which received no vaccine. After four weeks, roughly 40 % in the control group died from aneurysm rupture, whereas only 5 % of those injected with the vaccine died from rupture.
A tremendously interesting additional finding was that the vaccine helped to lower blood pressure. While blood pressure rose in the control mice, those that received the vaccine had a significantly lower blood pressure. This is exciting because most patients with high blood pressure must take four different medications, and a vaccine could dramatically reduce their daily medications. This means that Drs. Shah and Honjo are potentially on the cusp of developing a vaccine that may address plaque, potentially help reduce aneurysms, and may also lower high blood pressure.
Progress continues with the Apo A-1 Milano gene. As previously reported, this research has the potential to stop arterial plaque from growing as well as to shrink existing plaque. The discovery of a genetic protein product that rapidly shrinks plaque led to a small human study in 2003. This is an area that Dr. Shah has been pursuing for 18 years now, and he hopes to begin testing a delivery method in human clinical trials in the near future.
Dr. Shah has also been working with a plant biotech company called SemBioSys Genetics Inc. to produce the Apo A-1 Milano protein through an innovative and contaminant-free method using safflower seeds. The protein can be extracted and purified on a very scalable level for a relatively low cost. Progress continues, with the hope of bringing the product into clinical trials.
Using the same gene, Dr. Shah and his team have begun to follow an idea that may also impact Alzheimer’s research. Alzheimer’s is caused by a toxic protein that creates tangles that destroy nerve cells in the brain. One of the enzymes that leads to the toxic protein is affected by cholesterol as well as inflammation in the brain. Because the Apo A-1 Milano gene suppresses inflammation and pulls cholesterol out of cells, Dr. Shah has begun to collaborate with colleagues in other departments to gather pilot data that may help prevent Alzheimer’s Disease.
Dr. Shah, working with his colleagues Dr. Behrooz Sharifi and Dr. Lei Song, has developed a new model of dilated cardiomyopathy (heart muscle disease that can cause heart failure) in the mouse by deleting a key gene which raises the possibility that overexpression of that gene may prevent certain forms of cardiomyopathy. Furthermore, the same team, assisted by Lai Wang, have also developed a way of engineering new blood vessels from a mouse’s belly and along the way identified a unique population of cells in mouse’s belly that have the properties of stem cells or progenitor cells. Work is going on to assess the capability of these cells in regenerating vascular tissue.
As with patient care and teaching, biomedical research is a significant part of Dr. Shah’s life’s work. He and his dedicated team examine the underpinnings and biology of plaque build-up and the role of genes and genetic mutations. The pace and promise of such discoveries are likely to yield further medical insights and therapeutic breakthroughs that were unimaginable just one generation ago. Thanks to the efforts of physician researchers like Dr. Shah, this is an incredible period of learning, applying, and reimagining the possibilities of medicine for the benefit of humankind.
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