"Efforts to develop gene therapy for heart disease have been geared towards the elderly since they have fewer therapeutic options," says principal investigator Roger Hajjar, MD, of the Cardiovascular Research Center at MGH. "Our results show that we have some hurdles to overcome in order to optimize treatments in this population."
The researchers found that gene transfer by adenovirus is less efficient in aging rat heart cells than in cells from their younger counterparts. Over the years, adenoviruses have been used in laboratory and clinical research to deliver beneficial genes into their target cells. These modified viruses rely on several proteins on the surface of cells in order to gain entry and deliver therapeutic genes.
Hajjar's group had previously shown that aging cells are more resistant to entry by adenovirus than adult cells, but it had not been clear why. Through detailed laboratory experiments, the research team found that crucial proteins called integrins, which sit just under a cell's membrane, are scarce in older cardiac cells. It turns out that adenoviruses need these integrins to get into cells.
"The adenovirus binds to a receptor on the outside of a cell that is linked to integrins below the cell's surface," says Hajjar, who is an associate professor of Medicine at Harvard Medical School. "The receptor itself is abundant in older cells, but the integrins are deficient."
This may sound like bad news for the elderly, but Hajjar points out that it is possible to boost the expression of integrins. "The next step is to devise different ways of stimulating integrins specifically so you can still use low amounts of virus to deliver gene therapy," he says. Avoiding large doses of virus may be important because too much adenovirus could have a toxic effect on patients.
Hajjar says that the deficiency in integrins in the aging population may have a generally positive role in defending against viral infections. As people age, their immune systems weaken, and expressing fewer integrins may be a way to compensate. But of course, the cells cannot tell the difference between a therapeutic adenovirus and a disease-causing virus.
Hajjar and his colleagues plan to continue looking for ways to optimize gene therapy in aging cells with the hopes of making it a realistic treatment strategy for the elderly.
The other members of the research team are Fawzia Huq, MD, Djamel Lebeche, PhD, and Celine Mestel of the MGH Cardiovascular Research Center, Judith Gwathmey of Harvard Medical School, and Catherine Communal, PhD, of the Hopital Lariboisiere in Paris. The study was supported by funds from the National Institutes of Health, the American Federation for Aging Research, and the Fondation pour la Recherche Medicale.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $350 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, transplantation biology and photomedicine. In 1994, the MGH joined with Brigham and Women's Hospital to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups and nonacute and home health services.