PROGRESS REPORTS
Dr. Prediman K. (P.K.) Shah, MD, MACC
Shapell and Webb Family Chair in Clinical Cardiology
Director, Oppenheimer Atherosclerosis Research Center &
Atherosclerosis Prevention & Management Center at Cedars-Sinai Medical Center
Director, The Heart Foundation’s Steven S. Cohen Endowed Fellowship in Atherosclerosis Research
Professor of Medicine at Cedars-Sinai and UCLA
In August 2021, a phase 2 human clinical trial began to test a passive vaccine composed of Orticumab (a monoclonal antibody against oxidized LDL) in patients with both psoriasis and coronary atherosclerosis as they are at high risk for developing coronary artery disease, and Orticumab is likely to reduce both of these conditions. This is a randomized, double blind, placebo controlled pilot clinical trial, the gold standard for clinical trials. The trial is nearing completion, and we anticipate results in 2023.
We have also developed a nanoparticle based active vaccine formulation that successfully reduced atherosclerosis in a humanized mouse model. We continue our work to bring this nanovaccine to human clinical trials.
Other Current Research Projects
- We have identified a new gene called GATA3 that promotes visceral obesity, insulin resistance, and metabolic syndrome/Diabetes, all of which greatly contribute to the risk of cardiovascular disease. We are currently investigating whether we can prevent obesity and type 2 diabetes using Crisper-cas 9 gene editing. The support from The Heart Foundation for this project also helped us secure additional funding in the form of a peer- reviewed NIH grant.
- We are exploring the role of a newly discovered immunometabolite, 2 Hydroxyglutarate (2HG), in cholesterol-induced inflammation. This is highly relevant to atherosclerosis and this project will not only provide insights into how cholesterol induces inflammation, but it may lead to a new biomarker and potentially new therapeutic intervention. This work started in the laboratory of Dr. Ebru Erbay, a former colleague in the Smidt Heart Institute.
- We have identified a potential new supplement, alpha ketoglutarate, which may have a favorable effect on inflammation and atherosclerosis. Once again, support from The Heart Foundation for this project helped us secure additional funding in the form of a peer-reviewed NIH grant.
- We are studying the role of recently identified novel RNA-binding proteins (RBPs), which have important functions in the regulation of gene expression, in inflammation and the development of atherosclerosis. Dr. Paul Dimayuga and Dr. Xiaoning Zhao, The Heart Foundation’s Steven S. Cohen Endowed Fellow in Atherosclerosis Research, are spearheading this highly innovative work. Once again, support from The Heart Foundation for this project helped us secure additional funding in the form of a peer-reviewed NIH grant.
- We continue to work on gene therapy for Alzheimer’s disease based on our research on the Apo A-1 Milano gene and the discovery that carriers of this gene seem to be resistant to Alzheimer’s disease. We are currently engaged in a major project in collaboration with the neuroscience department with preliminary results expected in 2023.
As you know, The Heart Foundation has been supporting a number of research projects under my direction over the past 20 plus years. One of the main projects has been the development of a vaccine for atherosclerosis. There are two main components to the vaccine program:
- An active vaccine that uses immunization with LDL cholesterol related antigen to generate a protective immune response that slows down atherosclerosis
- A passive vaccine that uses injection of a synthetic antibody to slow down atherosclerosis
In January of 2021, we finally received FDA permission to launch a phase 2 human clinical trial to test a passive vaccine made up of a synthetic antibody (Orticumab) in patients with both psoriasis and coronary atherosclerosis. The reason for using psoriasis patients is that they are at high risk for developing coronary artery disease, and Orticumab is likely to reduce psoriasis as well as coronary atherosclerosis. This trial will be conducted in 70 patients at 15-17 US sites by Abcentra (a startup biotech company spun out by Cedars based on inventions in my lab). This is an exciting milestone. Check out this article to learn more.
As far as the active vaccine program is concerned, we have achieved a preclinical milestone in demonstrating that a nano-particle based active vaccine formulation reduces atherosclerosis in an animal model (the manuscript describing these exciting results is being prepared for submission to a medical journal for publication). Our eventual goal is that the nano vaccine will move into clinical testing in the foreseeable future.
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 atherosclerosis (plaque buildup in the arteries), a fatal illness at the root of most heart attacks, strokes and sudden deaths.
Thanks to the support of our generous donors who share our mission to develop more powerful and effective approaches to heart disease prevention and treatment, Dr. Shah and his research colleagues continue to make crucial progress in deepening our understanding of the diagnosis and prevention of atherosclerosis. Their discoveries will ultimately improve the lives of patients across the nation who are battling not only heart disease but also Alzheimer’s. Following is an update on the developments which have taken place in the laboratory over the last year.
Click here to download a PDF of Dr. Shah’s previous progress report.
Dr. P.K. Shah’s research of the mutant gene ApoA-1 Milano continues to make great progress. ApoA-I Milano is a naturally occurring mutant gene that encodes the ApoA-I Milano protein. As mentioned in past reports, this gene produces HDL, or high-density lipoprotein. Also called “good” cholesterol, HDL provides greater protection against atherosclerosis and vascular inflammation — conditions that result in clogged arteries, stroke and heart attack. In previous investigations, Dr. Shah and his team demonstrated that intravenous injection of this protein (manufactured by genetic engineering technology using bacteria as a factory) dramatically reduces plaque buildup and shrinks pre-existing plaque in animal models. Most recently, Dr. Shah and his team have shown that by using an innocuous virus, the ApoA-1 Milano gene was transferred into animals. Unlike the intravenous injection which must be repeated to maintain the protective effect of the HDL, this gene transfer allows the body to create its own supply of HDL. Using this gene therapy approach, Dr Shah’s lab has demonstrated that it shrinks existing plaque in animal models. He is now looking to partner with industry to bring this concept into human studies.
Dr. Shah and his team have also been making steady progress in developing ApoA-1 Milano gene transfer and gene-based therapy to prevent Alzheimer’s disease. In this effort, they are using gene transfer to the brain of mice genetically engineered to have Alzheimer-like pathology. A pilot study has shown favorable effects on the brain and no larger and longer studies are planned to confirm the preliminary results.
In his efforts to develop a vaccine for atherosclerosis, Dr. Shah is broadening his understanding of the immune system and the role it plays. As mentioned in previous reports, this work involves identifying specific antigens within cholesterol particles that provoke a protective immune response, allowing the development of an active vaccination strategy against cholesterol-plaque buildup. This active vaccine contains an antigen that when injected will stimulate the immune system to produce antibodies against the cholesterol particles. This vaccine against plaque build-up may also reduce high blood pressure and rupture of aortic aneurysm. In addition, Dr. Shah and his team have also pioneered the development of a passive cholesterol vaccine which involves the injection of a pre-formed antibody to reduce cholesterol plaque buildup inside arteries. This passive cholesterol vaccine (monoclonal antibody) has been tested and shown to be safe in a Phase 1 human trial. Plans are underway to initiate a Phase 2 efficacy human trial sometime in 2020.
Dr. Shah and his research team are currently participating in clinical trials of a new non-statin cholesterol lowering drug, Evanicumab, in patients with severe genetic defects causing them to have statin-resistant, very high cholesterol levels and a grave risk of premature death from heart disease.
Dr. Shah and his team have also identified a gene called GATA 3 which appears to regulate body metabolism and body weight and heart-scar formation after a heart attack in mouse models.
Project Update from Xiaoning Zhao, PhD
Recipient of the Steven S. Cohen Endowed Fellowship in Atherosclerosis Research
Through our Steven S. Cohen Endowed Fellowship in Atherosclerosis Research, under the direction of Dr. P.K. Shah, The Heart Foundation is training the next generation of extraordinary physician-researchers in cardiac medicine and paving the way for game-changing advances in atherosclerosis prevention.
Significant progress has been made in the project, led by Dr. P.K. Shah, to develop a vaccine against atherosclerosis. We successfully developed a new mouse model with a humanized immune response. These mice have T cells that are responsive to activation proteins found in human cells and will aid in further developing the vaccine that can generate the best immunologic memory to the p210 peptide vaccine in humans. The new mouse model is also important in designing tools that can be used to assess immune responses to the vaccine in humans. One such tool called pentamer technology will be used to track the generation of immunologic memory specific to the p210 vaccine. Thus, we are moving in a concerted effort to not only develop a vaccine testable in humans but also generate an assay to test for the efficacy of the vaccination.
In addition, our collaboration with Dr. Eun Ji Chung of the Department of Biomedical Engineering at USC to generate the p210 peptide nanoparticle vaccine is proving to be fruitful. Although faced with initial challenges, we have successfully tested the new vaccine formulation in non-humanized mouse cohorts. We are now testing the p210 nanoparticle vaccine in humanized mouse cohorts with the added goal of testing the utility of the pentamer technology to assess vaccine efficacy. This phase of the project is proving to be logistically challenging, but we are confident that we will be able to progress to the next stage.