PROGRESS REPORTS

Update on the Research of
Dr. P.K. Shah, MD, FACC, FACP, FCCP

Shapell and Webb Family Chair in Clinical Cardiology, Cedars-Sinai Medical Center
Director, Oppenheimer Atherosclerosis Research Center & Atherosclerosis Prevention & Management Center, Cedars-Sinai Medical Center
Director, The Heart Foundation’s Steven S. Cohen Endowed Fellowship in Atherosclerosis Research
Professor of Medicine, Cedars-Sinai and UCLA

Nearly a quarter century ago, Dr. Shah established the Oppenheimer Atherosclerosis Research Center at Cedars-Sinai Medical Center. Today, Dr. Shah and a team of 20 collaborators continue forging new ground in their efforts to identify the mechanisms leading to plaque buildup and to devise novel treatments for atherosclerosis, a fatal illness at the root of most heart attacks, strokes and sudden deaths.

Our ability to make a difference in the fight against atherosclerosis depends upon the philanthropic vision of partners like you who are committed to expanding new medical frontiers. Your support helps raise critical awareness of a condition that impacts millions of Americans every year, providing resources for scientific discovery with the potential to save lives across our community and beyond. As one of the nation’s top cardiologists, Dr. Shah has the skills and experience to transform our understanding of atherosclerosis, blazing a trail to innovation in research and clinical care. Over the past year, he has deepened his focus on the following key areas that may hold the secret to an atherosclerosis vaccine:

Development of ApoA-I Milano gene transfer and gene-based therapy for the prevention and reversal of cholesterol-plaque in the arteries
ApoA-I Milano is a naturally occurring mutant gene that encodes the ApoA-I Milano protein. The carriers of this mutant gene are all inhabitants of the northern Italian town Limone sul Garda. Dr. Shah’s laboratory has shown that intravenous injection of genetically engineered ApoA-I Milano dramatically reduces plaque buildup and shrinks pre-existing plaque in animal models. Dr. Shah and his team are exploring direct gene transfer as a way of exploiting the benefits of the ApoA-I Milano gene. These efforts are geared to transfer the gene directly into the body to prompt production of the protein naturally, eliminating the need to manufacture and deliver repeated intravenous injections. This past year, the team was able to show that by using an innocuous virus called AVV8, they can successfully deliver the ApoA-I Milano gene into the body of animals. This new type of transference resulted in the animals’ ability to start producing the protein which inhibits plaque build-up. Infusion of the ApoA-I Milano protein is currently being tested in human subjects in a proof-of-concept Phase IIA clinical trial.

Development of ApoA-I Milano gene transfer and gene-based therapy for the prevention of Alzheimer’s disease
Dr. Shah and his team are piloting an experimental project to examine whether the potent anti-inflammatory effects of the ApoA-I Milano gene can be used to eradicate Alzheimer’s disease in an animal model. They have recently developed preliminary proof of efficacy showing that ApoA-I Milano gene transfer to the brain using an intravenous injection of the gene attached to an innocuous virus is able to reduce amyloid fibril deposits. In tandem with neuroscience researchers, they are currently testing the efficacy of ApoA-I Milano gene transfer in an animal model of Alzheimer’s disease on cognitive function and brain pathology. The team is modifying their gene transfer approach to enhance the expression of protective proteins in the brain.

Role of the immune system in atherosclerosis and development of a vaccine for atherosclerosis

The team’s research to develop an atherosclerosis vaccine is getting closer to human studies. Collaborative work in animal models has identified components of LDL cholesterol (so-called “bad” cholesterol) particles that act as antigens to which the immune system reacts, producing antibodies and cellular reactions that may have the potential to reduce plaque buildup. Some of these antigens, when incorporated into a vaccine formulation, were shown to reduce plaque buildup without changes in blood cholesterol levels, thus raising the possibility that a vaccine against plaque build-up could be developed. Work continues to refine these findings, and they hope to obtain permission from the FDA to test a human-compatible vaccine formulation within the next couple of years.

Identification and testing of novel athero-protective and athero- permissive genes using transcriptional profiling of athero-prone and athero-resistant arteries
Dr. Shah continues working toward important discoveries with significant implications for novel, gene-based therapeutics to prevent atherosclerosis. Through an examination of the genetic expression patterns of athero-prone and athero-resistant arteries, he has found novel expression patterns that are unique to either coronary or mammary arteries. This is important because previous research showed coronary and carotid arteries are remarkably susceptible to atherosclerosis, yet internal mammary arteries and radial arteries are almost absolutely resistant to it. Dr. Shah’s work builds on the discovery of several novel genes that may provide clues as to why this is so; those genes include pleiotrophin (PTN).

Project Update from Xiaoning Zhao, PhD

Recipient of the Steven S. Cohen Endowed Fellowship in Atherosclerosis Research

Dear Supporters of The Heart Foundation,
As recipient of the Steven S. Cohen Endowed Fellowship in Atherosclerosis Research, I am providing this update on our research progress over the past year – progress made possible by support from you and The Heart Foundation.

The project, led by Dr. P.K. Shah to develop a vaccine against atherosclerosis, continues to move ahead. I would like to highlight two important developments:

First, my colleagues and I have successfully demonstrated that the p210 peptide vaccine is able to alter the immune response to atherosclerosis in an animal model. We had hypothesized that since apoB-100 is a protein endogenous to the self (it is a self-protein, as opposed to an infectious protein), then the immune system should have had previous exposure to peptide fragments of the protein, such as p210. Such exposure by the immune system generates what is called immunologic memory. Using tetramer technology that is able to identify T cells with immunologic memory specific to p210, we were able to demonstrate that a small population of CD8+ T cells are present in animals with atherosclerotic disease, and that the number of these p210-reactive CD8+ T cells increased as the disease got worse. Importantly, when the animals were immunized with the p210 vaccine, the immunologic memory of the p210-reactive CD8+ T cells dramatically changed, with changes also observed in the profile and functional behavior. We were able to link these immunologic changes with the reduction in atherosclerosis. This provides the conceptual background for what to potentially expect when the p210 is tested for clinical use. These results have been presented at an international conference and were published in the Journal of the American Heart Association this past July.

Second, we have successfully tested a new formulation of the p210 vaccine that is potentially optimized for clinical use. Dosing and kinetic studies have been accomplished using a new adjuvant called Montanide. It is a new generation of water in oil emulsion as adjuvant for human vaccines. Use of the p210 vaccine formulated with Montanide has shown positive results in an animal model. We are awaiting the outcome of a replication study for confirmation. If reproducible, then we believe we have a vaccine formulation that can be proposed for clinical testing.

My colleagues and I hope to see the concept of a vaccine for atherosclerosis tested in the clinic. I believe we are now closer to that goal.

Thank you again for your support!

Sincerely yours,
Xiaoning Zhao, PhD
Project Research Scientist
Oppenheimer Atherosclerosis Research Center, Division of Cardiology, Cedars-Sinai Smidt Heart Institute