CDU

With the salient risk factor for development of cardiovascular disease being advancing old age, research cardiologist Roger Hajjar notes that efforts to develop gene therapy for heart disease "have been geared toward the elderly, since they have fewer therapeutic options." Experimental gene therapy for heart failure and chronic heart-muscle diseases have been tried by many researchers for many years, but so far without signal therapeutic success. It has been limited largely by the low efficiency of gene transfer delivered by traditional viral vectors.

Hajjar, of the Cardiovascular Research Center at Harvard-affiliated Massachusetts General Hospital (Boston, Massachusetts), is senior author of an article in the journal Circulation, released online in early March. "Our findings show that in the aging heart there is a tenfold decrease in efficiency of gene transfer," Hajjar said. "If gene transfer as a therapeutic modality is going to be used in the aged population, obviously there's a problem, because the efficiency is going to be so low. Gene therapy in heart failure is going to be used mainly in the elderly population, because that's where heart failure is endemic."

Hajjar defines the three cardiac ages of man (and woman) as birth to age 18; 18 to 60 or 65; the elderly above 65. "Our study shows that there's a decrease in the efficiency of the gene transfer in this [latter] population." He said that most of the preclinical gene therapy trials that are done "are usually performed on adult animals, and then they're translated clinically into elderly or older populations." The impending human clinical trials, which Hajjar said should begin in about two years, "are going to be performed in elderly populations where heart failure is so prevalent."

What the paper implies, he said, "is that when we go for clinical trials to treat heart failure in this elderly human population, we'll not only deliver the vectors conveying the gene products but something also to stimulate the factor integrin, which will allow improved gene transfer efficiency." So far, Hajjar said, "we have had no human trials for heart failure. The clinical studies are being planned right now by a number of companies and clinical centers like ourselves."

He said that the forthcoming cardiac gene therapy approach is not anything like open-heart surgery, "but by catheter just like a cardiac catheterization where the catheter is threaded all the way to the heart." Hajjar said the researchers contemplate using catheters to inject the gene therapy vector into the heart via the arteries. "It's not like a coronary bypass, because you have to deliver right into the heart."

He said his group's research revealed why the decrease in efficiency of gene transfer in the elderly is occurring. "The reason is not the receptor for the viral vector on the cardiac cells ... These modified viral vectors rely on several proteins on the cell surfaces in order to gain entry and deliver therapeutic genes." Rather, he said, "it's the machinery that comes after the receptor, which is known as the alpha-3 integrin."

Hajjar said that in this cardiac context, the role of integrin is as a bridge between the receptor of the vector and the cardiac intracellular space. "That's where the vector comes in and releases the gene product, which then makes the protein of interest that you're trying to get," he said. "Interestingly, these integrins can be stimulated to have higher expression and better efficiency. So our goal is to devise methods that could increase the efficiency of gene transfer in this aging population by stimulating their integrin." He added, "These crucial proteins, which sit just under a cell's membrane, are scarce in older cardiac cells."

The Circulation article cited the gene product as "just a reporter, or marker, gene green fluorescent protein which glows just to visualize the transfer efficiency." For therapeutic effects, Hajjar said, "we have other genes as well that are going to be tested. The gene transfer product is carried by the adenovirus and its receptor. It also uses the coxsackie adenovirus receptor to bring it in. The coxsackie virus carries a dual receptor vector, but we don't use the virus itself for gene therapy; it's too toxic. We only use the adenovirus for gene therapy."

For anyone working on gene transfer in the heart, Hajjar said, "the novel aspect of our findings that the adenovirus vector, which we use for gene therapy, is less efficient in aging cardiac cells than it is in adult cells. There's a tenfold difference. So anyone going to clinical trials in this elderly population with the adenovirus as vector is going to get a decrease in efficiency." He added, "We're working at improving that efficiency."

In the researchers' in vivo experiments, Hajjar said that the elderly rodent "has a much lower efficiency. Our 26-month-old aging rat is like an 80-year-old human." Those rat experiments netted three results, he said: "The decreased efficiency, that the integrins are the factors responsible for the decrease, and we can stimulate these integrins to actually improve the efficiency."

In terms of biotechnology companies that are planning human gene therapy in the cardiac-disease world, Hajjar said "a negative result from their studies may be due to this decreased efficiency, and not because of the biology they're trying to alter."