Cardiologists frequently treat heart disease patients now by using stents to expand partially blocked blood vessels and improve blood flow. However, new obstructions may gradually form within the stents themselves and dangerously narrow the passageway. A newer generation of stents releases drugs to counteract this renarrowing process, called restenosis, but the polymer coatings that initially hold the drugs to the stents may stimulate inflammation. The inflammation in turn leads to restenosis.
Researchers at The Children's Hospital of Philadelphia have developed a novel technique to attach therapeutic genes to a stent's bare metal surface. This technique allows the genes to help heal the surrounding blood vessels, while avoiding the inflammation caused by polymer coatings.
The research team reported their proof-of-principle study, using cell culture and animal models, in the early edition of the Proceedings of the National Academy of Sciences, published online this week.
"This is the first study to demonstrate successful delivery of a gene vector from a bare metal surface," said senior author Robert J. Levy, M.D., the William J. Rashkind Chair of Pediatric Cardiology at The Children's Hospital of Philadelphia. A gene vector is a biological substance, in this case an adenovirus, capable of delivering a therapeutic gene to target cells.
Dr. Levy's team created a unique water-soluble compound, polyallylamine biphosphonate, that binds to the stent's metal alloy surface in a layer with the thickness of only a single molecule. The biphosphonate holds and gradually releases adenovirus particles of the type used to deliver therapeutic genes.
In cell cultures, the adenovirus successfully delivered genes from alloy samples to animal arterial smooth muscle cells. In a second experiment using rodents, the researchers detected gene expression with significantly lower restenosis in the carotid arteries of animals with the experimental stents, compared to control animals with conventional, polymer-coated stents.
The researchers used a therapeutic gene that encodes for a protein, inducible nitric oxide synthase (iNOS), in the carotid artery studies, because of iNOS's ability to control cell damage in blood vessels. "However, in further studies, one might use a combination of therapeutic genes or different gene vectors, for even better results," said Dr. Levy.
Metallic implants are already widely used in medicine. Some examples are artificial joints and orthopedic pins and rods, pacemaker electrodes, and titanium tooth implants. "The results of our study may have broader implications for other diseases in which implantable medical devices may be used to deliver gene therapy," said Dr. Levy.
Dr. Levy's co-authors included Ilia Fishbein, M.D., Ivan S. Alferiev, M.D., Origene Nyanguile, Richard Gaster, and Howard Felderman, of the Children's Hospital Division of Cardiology. Co-authors from the University of Pennsylvania were John M. Vohs and Gordon S. Wong, of the Department of Chemical and Biomolecular Engineering; Hoon Choi and I-Wei Chen, of the Department of Material Science and Engineering; and Robert L. Wilensky, of the Cardiovascular Division of the Hospital of the University of Pennsylvania.
Grant support came from the National Heart, Lung and Blood Institute, the Nanotechnology Institute, and both the William J. Rashkind Endowment and Erin's Fund of The Children's Hospital of Philadelphia.
About The Children's Hospital of Philadelphia: The Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking second in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 430-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit www.chop.edu.
Journal
Proceedings of the National Academy of Sciences