Dr. Prediman K. (PK) Shah, M.D.
Cedars-Sinai Medical Center

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Davis Wright Tremaine is pleased to feature Dr. Prediman K. (PK) Shah, M.D. as our “Inventor in the Spotlight.” Dr. Shah is Director of the Division of Cardiology and the Atherosclerosis Research Center at Cedars-Sinai Medical Center, where he holds the Shapell and Webb Family Endowed Chair in Cardiology. Dr. Shah and his laboratory have played a key role in developing an array of innovative approaches for the treatment of atherosclerosis.

Despite decades of medical research, heart disease kills more people than the next 16 diseases combined, and is a problem that many medical practitioners face on a daily basis. This grim statistic is one of the reasons that Dr. Shah became interested in cardiology. Following medical school in Kashmir, India, Dr. Shah completed internship and residency training in India and in the United States. He then underwent fellowship training for two years in clinical cardiology at the Montefiore Hospital of Albert Einstein College of Medicine in New York City, followed by another year of research fellowship in cardiology at Cedars-Sinai, where he became a faculty member the following year. In addition to his position at Cedars-Sinai, Dr. Shah holds a faculty appointment as Professor of Medicine at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA).

While Dr. Shah is well-known to medical practitioners in the area of cardiology (he has published over 250 scientific papers and abstracts), he is also a prominent spokesman and educator on issues relating to heart disease for the non-medical community. Dr. Shah has appeared several times as a guest on Larry King Live, and has also been featured in programs on 60 Minutes, The Learning Channel, and on PBS.

The main focus of Dr. Shah’s research is to improve our knowledge regarding the molecular mechanisms of atherosclerosis and to develop novel treatments for its prevention, stabilization and reversal. Atherosclerosis is the deposition of a fatty material, called plaque, on blood vessel walls leading to narrowing of blood vessels and obstruction of blood flow to the heart, brain, and limbs. Plaque is a combination of cholesterol, fatty acids, calcium, scar tissue, and blood components that stick to the inside of the arterial wall. Some plaques are unstable and can rupture or burst, leading to blood clotting inside the artery. If a blood clot blocks an artery completely, blood flow may be stopped, which results in heart attack and/or stroke.

Cholesterol levels in the bloodstream have long been linked to atherosclerosis. While cholesterol is an intrinsic part of cell membranes and is a precursor to important hormones such as estrogen and testosterone, an elevated level of cholesterol in the blood is associated with an increased risk of atherosclerosis.

Cholesterol is highly insoluble in water, so in order to be transported around the body, it needs to be packaged in complexes called “lipoproteins” that consist of cholesterol, fatty acids, and proteins. There are different types of lipoproteins found in the bloodstream. Low-density lipoprotein (LDL) is a form of cholesterol generally considered to be detrimental to one’s health, and is often referred to as “bad cholesterol.” High-density lipoprotein (HDL) is often referred to as “good cholesterol;” the level of circulating HDL is inversely proportional to the incidence of coronary artery disease. Therefore, many medical treatments for atherosclerosis have focused on decreasing the levels of LDL and increasing those of HDL.

However, Mother Nature has provided a remarkable exception to this rule. In 1980, a family from Limone sul Garda in Northern Italy was found to have high levels of Triglycerides and extremely low levels of HDL, a pattern that is normally associated with a markedly increased risk of development of atherosclerotic vascular disease. Despite this alarming lipoprotein profile, members of this family showed no signs of heart disease.

Upon further analysis, it was discovered that many members of this Italian community had a mutation in the gene specifying ApoA-I, one of the main proteins associated with HDL that is involved in transporting cholesterol in the bloodstream. Additional testing was performed, and it was found that approximately 40 out of the nearly 1,000 people tested in the Limone sul Garda area had this mutation. These findings suggested that the mutant form of ApoA-I somehow protected these people from the damage normally associated with an unhealthy lipid profile. This mutant version of ApoA-I was identified by researchers Cesare Sirtori and Guido Francheschini of the University of Milan thus named “ApoA-I Milano.”

The evidence for the protective quality of ApoA-I Milano remained largely speculative until 1994, when Dr. Shah and his laboratory tested a synthetic form of HDL containing ApoA-I Milano. They used this genetically engineered synthetic HDL to treat rabbits that had been fed a high cholesterol diet. The results were dramatic; treatment of rabbits with ApoA-I Milano markedly reduced arterial plaque buildup. Additional studies were carried out in mice, where it was shown that a single dose of ApoA-I Milano could remove cholesterol and inflammation from an arterial plaque within 48 hours. It was also shown that repeated treatment over five weeks could arrest the progression of plaque build up, and that higher doses could even reverse pre-existing plaque. While many drugs used to treat atherosclerosis stabilize or prevent the growth of plaques, Dr. Shah’s synthetic HDL with ApoA-I Milano appreciably reversed the plaque formation process, reducing existing plaque and allowing restoration of blood flow.

Based on these successes, a small, proof of concept-type phase 2 clinical trial was conducted by physicians from the Cleveland Clinic to test the effects of ApoA-I Milano in humans. Forty-seven patients that were recovering from a heart attack were enrolled in the trial. Using intravascular ultrasound technology, coronary plaque size was measured in the patients both prior to and five weeks after initiation of treatment. Thirty-six patients received weekly intravenous infusions of synthetic HDL containing ApoA-I Milano whereas 11 received a placebo. After five weeks, significant shrinkage of existing coronary plaque was observed in the patients who received the synthetic HDL. Larger clinical trials are underway, and it is expected that definitive results will be acquired in 2-3 years.

An alternative approach to introducing ApoA-I Milano by intravenous injection is gene therapy, a process wherein the gene or DNA specifying ApoA-I Milano is introduced into the body where it becomes a part of the genetic makeup of cells, instructing the cells to produce their own supply of ApoA-I Milano. Dr. Shah’s laboratory has already done substantial work in this area, demonstrating the feasibility and efficacy of gene therapy in animal models using delivery of the gene, carried by an innocuous virus serving as a carrier, through the bone marrow stem cells or by a single intramuscular injection. Dr. Shah is currently assessing the durability of the benefits of gene therapy as well as its safety in animal models with plans to bring this approach to human testing within the next 2-3 years.

Another innovative approach against atherosclerosis being undertaken in Dr. Shah’s laboratory, in collaboration with Dr. Jan Nilsson of Sweden, is the production of a vaccine that will use the power of the immune system to combat atherosclerotic plaques. Vaccines, which are commonly used to produce immunity to diseases such as those caused by viruses and bacteria, work by teaching the immune system to “recognize” and “remember” entities that are foreign or harmful. After the body is initially introduced to a foreign entity or compound in a vaccination, the immune system can later “recognize” the compound and mount a response to destroy it.

In the case of atherosclerotic plaques, patients would be vaccinated with one of the components present in plaques, such as portions of oxidized LDL cholesterol, or part of the protein component of LDL. Following the vaccination, the patient’s immune system may then “recognize” those components, and mount an immune response against them, leading to inhibition of atherosclerotic plaque build-up.

Drs. Shah and Nilsson have carried out a vaccine study using rabbits that were fed a high-cholesterol diet. The rabbits, which were vaccinated with oxidized LDL-cholesterol, later showed a 70% reduction in plaque buildup in comparison to the unvaccinated rabbits. These results are especially promising because they suggest that vaccines that recognize components of atherosclerotic plaques may lead to the reduction of plaques without impacting cholesterol levels. More recently, Drs. Shah and Nilsson have used new vaccines made from synthetic peptides designed to simulate antigens within the protein portion of LDL-cholesterol, and have shown them to be effective in reducing plaque build-up in mouse models of atherosclerosis. Human testing of these peptide vaccines is anticipated within the next 3-4 years.

Using a variety of different experimental approaches, Dr. Shah has been instrumental in developing new therapies that promise to increase the treatment options and improve the outcomes for millions of people who are coping with atherosclerosis and cardiovascular disease. We congratulate Dr. Shah and his team on their accomplishments, and wish them continued success.

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