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Pennsylvania Hospital surgeon receives grant to develop molecular cardiac surgery

Charles Bridges, MD, ScD, Associate Professor of Surgery at the University of Pennsylvania Medical Center and Chief of Cardiothoracic Surgery, Pennsylvania Hospital, has been awarded a $3 million grant from the National Heart, Lung and Blood Institute for his work in molecular cardiac surgery: a unique approach to gene therapy for heart failure.

The four-year grant will enable Dr. Bridges to expand upon his current research in large-animal molecular cardiac surgery (a term coined by Dr. Bridges). This methodology could provide alternatives both to heart transplantation and to the use of permanent mechanical-assist devices in some humans with end-stage heart failure. Molecular cardiac surgery, if successful, will be more powerful therapeutically and avoid the problems of rejection, infection, increased stroke risk and device failure often associated with these existing technologies.

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 U.S. 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," says 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.


Contact: Lee-Ann Landis
University of Pennsylvania School of Medicine

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