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$14.3 Million Federal Grant Fuels Cardiovascular Gene Therapy Program at the University of Pittsburgh

PITTSBURGH, January 2, 2001 — The University of Pittsburgh has received a five-year, $14.3 million federal grant for initiatives to treat cardiovascular diseases using gene therapy.

The grant, from the National Heart, Lung and Blood Institute (NHLBI), establishes the Cardiovascular Gene Therapy Center to focus on clinical and laboratory studies on the number one health threat in this country. It also designates Pitt's Human Gene Therapy Applications Laboratory as the only national facility for producing vectors, or gene transport systems, used in all future NHLBI-funded clinical gene therapy studies, and provides for training of future clinicians/scientists in the latest gene therapy technologies and procedures.

The grant is the largest of only four awarded nationally by the NHLBI.

“This program project grant is a result of many years of basic and clinical research in gene therapy at the University of Pittsburgh School of Medicine, and it recognizes the university’s world leadership in the design and implementation of gene therapies for cardiovascular disease,” stated Arthur Levine, M.D., senior vice chancellor for health sciences and dean of the University of Pittsburgh School of Medicine.

"We expect that results of funded pre-clinical and clinical studies will have a dramatic and lasting impact on the way cardiovascular disease is treated in the future."

“The University of Pittsburgh is an important component of this new NHLBI initiative – The Programs of Excellence in Gene Therapy. The grants are designed to establish safe and effective ways of translating the best scientific research into a viable clinical approach for these devastating cardiovascular diseases,” said NHLBI Director Claude Lenfant, M.D.

Gene therapy has great potential to treat a variety of cardiovascular diseases of the heart, lungs, blood vessels and blood. It could also be used one day to help prevent cardiovascular disease from ever affecting many of the millions of people destined to develop some form of it each year in the United States.

Since gene therapy was first used in the clinic 10 years ago for a rare immune disorder, it has evolved considerably and been applied to a variety of diseases. In the last six years alone at the University of Pittsburgh, clinical investigators have applied this technology to problems ranging from heart disease to cancer.

Although commercial manufacturers developed some of these treatments, university scientists created many gene therapies now in use at the University of Pittsburgh Medical Center. Clinical trials have included novel therapies for an inherited metabolic disorder and for cancers of the breast and brain. In 1996, the University initiated the world’s first arthritis gene therapy based on research conducted at the institution.

“These milestones testify to the caliber of gene therapy investigations at the University of Pittsburgh and lend us the credibility to produce clinical grade vectors for use by our institution and other academic centers,” remarked Joseph Glorioso, Ph.D., principal investigator for the grant and chairman of the department of molecular genetics and biochemistry.

“Not only will our expertise in this field expand the frontier of gene therapy for the number one health threat in this country; it will accelerate our transfer of commercially marketable biotechnologies.”

Gene therapies rely on the use of “vectors,” or transport systems, to introduce new genes into the body. These genes produce therapeutic proteins that replace, augment or alter existing cellular activities to create a healthier environment. Gene therapy effects can be temporary or long-lasting depending on how a particular therapy is designed.

The University of Pittsburgh has developed an extensive array of vector systems that can enter different cells. Many of these vectors are viruses that have the natural ability to infect certain cells and deliver their genetic cargo. These viruses are engineered to make them safe for use in the clinic.

"Unlike traditional pharmacologic approaches, gene therapy can permit the sustained local delivery of a therapeutic gene product, often without systemic effects on the patient. While drug therapy typically requires frequent dosing, a single gene therapy application may be adequate to prevent, attenuate or reverse chronic disease processes," said Timothy Billiar, M.D., chairman of the department of surgery and a principal investigator in the study.

"This grant will build on our many years of pre-clinical gene research. We are ready to take the next step and move forward to expand gene therapy."

Despite dramatic advances in the prevention, diagnosis and treatment of cardiovascular disease made during the last half of the 20th century, it remains the number one cause of morbidity and death in the United States. For example, heart failure is a disease of epidemic proportions in the United States, affecting more than five million people. It accounts for more than one million hospitalizations, 400,000 deaths and $40 billion in health care expenses each year. Less than half of those diagnosed with one form of heart disease, congestive heart failure, live five years.

"We are at a major crossroads in understanding the basic biology related to cardiovascular disease and applying that knowledge to the development and use of very sophisticated, targeted therapies,” added Arthur Feldman, M.D., Ph.D., Harry S. Tack professor of medicine at the University of Pittsburgh School of Medicine, director of the Cardiovascular Institute at University of Pittsburgh Medical Center and a principal investigator in the study. "These studies will help determine if we can make positive changes in the heart over the long-term."

The grant is a collaboration of many departments at the University of Pittsburgh School of Medicine including the Department of Molecular Genetics and Biochemistry, the Department of Surgery and the Cardiovascular Institute. It will fund two clinical trials, three pre-clinical research studies and a training program in gene therapy.

One clinical trial will investigate gene therapy to heal poorly functioning hearts of patients who are so ill that they must be implanted with an assist device to help pump blood throughout the body. University investigators believe that a temporary combination of gene therapy with the support of a left ventricular heart assist device may allow a patient’s heart to heal and eliminate the need for some patients to receive an organ transplant.

In a second clinical study, doctors will determine whether gene therapy prevents long-term damage in blood vessels called intimal hyperplasia. Bypass surgery and many other cardiovascular procedures routinely use blood vessels that are removed from one part of the body and grafted into another area of the body to improve blood flow. Removing and relocating these healthy vessels often traumatizes them by setting off a cascade of molecular events that result in inflammation and tissue regrowth that eventually occludes blood vessels and restricts blood flow. Gene therapy delivered during a revascularization procedure may prevent the eventual demise of the healthy vessels.

The three pre-clinical projects will encompass a variety of basic investigations.

In one project, investigators will develop methods for targeting one viral vector, herpes simplex virus type 1 (HSV-1), to cardiovascular tissues by directing the virus to attach to receptors found on cells of the blood vessels and heart. The second pre-clinical study will address the application of gene therapies to alter the way tissues remodel when the heart weakens, dilates and fails to pump blood effectively. The third preclinical project will develop a viral vector capable of transferring the human inducible nitric oxide synthase (iNOS) gene to suppress the development of long-term vasculopathy, the deterioration of blood vessels that is the primary cause of heart transplant failure.

The final component of the grant will provide advanced training and education to clinician scientists to pursue an academic career in translational research related to cardiovascular gene therapy.

The goal of the training core, directed by David A. Geller, M.D., Samuel P. Harbison assistant professor of surgery, is to train physicians to conduct clinical gene therapy trials targeting cardiovascular disease. Dr. Geller, who is internationally recognized for his cloning and characterization of the human iNOS gene, also has an active interest in gene therapy related to liver transplantation.

The gene transfer vectors will be produced in the Human Gene Therapy Applications Laboratory under the direction of John A. Barranger, M.D., Ph.D., professor in the departments of human genetics, pediatrics and molecular genetics and biochemistry. Dr. Barranger will work with the principal investigators to develop biologically active adenoviral and adenoassociated viral (AAV) vectors for clinical trials. He also will participate in the design and monitoring of toxicologic studies of adeno and adenoassociated viral vectors.

In consultation with Xiao Xiao, Ph.D., assistant professor in the department of molecular genetics and biochemistry, and co-investigator, Dr. Barranger will direct the development of methods to produce and purify clinical scale vector lots of AAV vectors. Dr. Xiao developed many of the AAV vector systems and methods for their production.

Additional University of Pittsburgh clinicians and researchers involved in the project grant include: Qing Bai, Ph.D.; James Borowski; Robert Branch, M.D.; Saverio Capuano, D.V.M.; Neal DeLuca, Ph.D.; Katherine M.Detre, M.D., Dr.P.H.; Romesh Draviam; Carol Frye; William Goins, Ph.D.; Patsy Guzzi, Jr.; Nancy E. Harter; Richard Holubkov, Ph.D.; Andrzej Janczewski, Ph.D.; Wishwa Kapoor, M.D., M.P.H.; David Kopp; Robert Kormos, M.D.; Bonnie Lemster, B.S.; Songhui Li, M.S.; YunYou Li, Ph.D.; Yin Lin, Ph.D.; Michel S. Makaroun, M.D.; Deborah E. Martin, B.A.; Jeffrey P. Martin, M.B.A.; Kenneth R. McCurry, M.D.; Dennis McNamara, M.D.; Charles McTiernan, Ph.D.; Michael A. Murphey-Corb, Ph.D.; Virginia Reeser, P.A.; Steven E. Reis, M.D.; Paul Robbins, Ph.D.; Bernard Sakmar; Virginia M. Schneider, R.N.; Larry L. Shears, M.D.; Donna Beer Stolz; William Swaney, M.S.; Yoram Vodovotz, Ph.D.; Zhiliang Wang, M.D.; Simon C. Watkins, Ph.D.; David Watkins, M.D., Ph.D.; Darren P. Wolfe, Ph.D.; and Jennifer Zazzera.

Other NHLBI program project grant recipients include Stanford University, The University of Washington (Seattle) and Weill Medical College of Cornell University.

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