Genes, which are carried on chromosomes, are the basic units of heredity. They produce proteins that directly or indirectly carry out all life functions. When genes are absent or defective, proteins are unable to carry out their normal functions, resulting in genetic disorders. In gene therapy, a functioning gene replaces an absent or faulty gene, so that the body can make the correct protein and consequently eliminate the root cause of a disease.
Using molecular cardiac surgery, Dr. Bridges' group was the first in the world to convincingly demonstrate that marker genes could be efficiently inserted into the majority of heart muscle cells in large animals like dogs and sheep. What makes this approach so unique is that Dr. Bridges' group uses a novel, patent-pending cardiac surgical procedure and specially designed hardware as a platform for the most efficient delivery of genes to heart muscle cells ever achieved in large animals. Prior to Dr. Bridges work, research in other laboratories had not proved successful in achieving global, heart-specific gene expression in animals other than rodents and mice.
The molecular cardiac surgical approach has an added advantage since genes are expressed only in the heart, enhancing the safety of this approach over all other available gene delivery methods. The preliminary success of molecular cardiac surgery opens the door to developing new treatments for a variety of heart muscle diseases causing heart failure.
A carrier called a vector is used to deliver the specially designed beneficial genes - "transgenes". The most common vector is a virus that has been genetically altered. Viruses have evolved ways of delivering their genes to human cells in a pathogenic manner. Researchers have taken advantage of this capability by removing disease-causing genes from the virus and inserting therapeutic genes. The vector then discharges the therapeutic genes into the target cell. The new grant will enable Dr. Bridges to move beyond his work with marker genes and begin testing his findings using therapeutic genes in sheep with heart failure.
Dr. Bridges closely collaborates with Hansell Stedman, M.D., Associate Professor of Surgery at the University of Pennsylvania. Dr. Bridges and Dr. Stedman jointly have several United States and international patents for the efficient use of vectors in gene delivery to cardiac and skeletal muscle. Prior to their work, delivery techniques in common use typically resulted in one-to-two percent expression of therapeutic genes in the target cells. Dr. Bridges and Dr. Stedman generate successful delivery rates approaching 100 percent in both skeletal and cardiac muscle. In addition, their delivery methods enable safe removal of the delivery device once the therapeutic genes are delivered. This substantially reduces the risk of harm to other organs in the body.
"This grant will enable us to build on the advances my colleagues and I have been fortunate to achieve", stated Dr. Bridges. "Molecular cardiac surgery offers genuine promise for eventually prolonging and enhancing the quality of life for many patients with heart disesase."
Dr. Bridges' new study under the National Heart, Lung and Blood Institute grant will focus on one of the most promising transgene candidates with potential for healing the heart. Specifically, up to 100 trillion genes will be delivered to each heart, which is expected to arrest the progression of heart failure and possibly lead to recovery of heart function within several weeks.
Dr. Bridges is Chief, Division of Cardiothoracic Surgery, at Pennsylvania Hospital and associate professor of surgery at the University of Pennsylvania School of Medicine. Dr. Bridges graduated from Harvard College at age 19 and received his M.D. degree from Harvard University, and a doctorate in chemical engineering from M.I.T. He completed his residency in general surgery and his fellowship in cardiothoracic surgery at the Hospital of the University of Pennsylvania. He is board certified in thoracic surgery and in general surgery.
Dr. Bridges is the Chairman of the Society of Thoracic Surgeons Workforce on Evidence-Based Surgery. He is a fellow in the American College of Surgeons, the American Heart Association, and the American College of Cardiology and was the founding President of the Association of Black Cardiovascular and Thoracic Surgeons.
PENN Medicine is a $2,9 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine - founded in 1765 as the United States' first medical school - and the University of Pennsylvania Health System.
Penn's School of Medicine is ranked nr. 2 in the United States for receipt of NIH research funds; and ranked nr. 3 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System includes three hospitals, all of which have received numerous national patient-care honours - Hospital of the University of Pennsylvania; Pennsylvania Hospital, the United States' first hospital; and Penn Presbyterian Medical Center; a faculty practice plan; a primary-care provider network; two multi-speciality satellite facilities; and home care and hospice.