An estimated 1.1 million people a year in the U.S. suffer heart attacks, which kill 40 percent of them. Cardiac disease is the single greatest cause of morbidity and mortality in Western industrial societies. And the salient risk factor for development of cardiovascular disease is advancing old age.
"Short of a heart transplant," observed research cardiologist Roger Hajjar, "are typical heart failure medications such as beta-blockers, angiotensin-converting enzyme inhibitors, diuretics and digoxin. Efforts to develop gene therapy for heart disease," Hajjar pointed out, "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's 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 - is senior author of an article in the journal Circulation, released online March 4, 2003. Its title: "Decreased efficiency of adenovirus-mediated gene transfer in aging cardiomyocytes."
"Our just-published findings," Hajjar told BioWorld Today, "show that in the aging heart there is a 10-fold decrease in efficiency of gene transfer. Now, 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 population.
"Most of the preclinical gene therapy trials that are done," he added, "are usually performed on adult animals, and then they're translated clinically into elderly or older populations. When we are testing gene transfer we are doing so in adult animals. However, the impending human clinical trials are going to be performed in elderly populations where heart failure is so prevalent. They should begin about two years from now."
Integrin: An Added Efficiency Factor
"What our paper implies," Hajjar continued, "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 we have had no human trials for heart failure. The clinical studies are being planned right now by a number of biotech companies and clinical centers like ourselves."
Hajjar explained 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. We contemplate using catheters that go from the patient's groin all the way up to the coronary arteries feeding the heart, then injecting 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.
"We went ahead with our research," Hajjar recounted, "and found out why this decrease in efficiency is occurring. The reason is not the receptor for the viral vector on the cardiac cells; the receptor if anything is upregulated. These modified viral vectors rely on several proteins on the cell surfaces in order to gain entry and deliver therapeutic genes. It's the machinery that comes after the receptor, which is known as the alpha-3 integrin.
"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. 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. These crucial proteins, which sit just under a cell's membrane, are scarce in older cardiac cells. The adenovirus vectors need these integrins to get into cells.
"In our paper," Hajjar noted, "the gene product is just a reporter, or marker, gene - green fluorescent protein - which glows just to visualize the transfer efficiency. For therapeutic effects, 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."
In Upcoming Human Trials, Efficiency Unlikely
"For anyone working on gene transfer in the heart," Hajjar said, "the novel aspect of our findings is 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 10-fold difference. So anyone going to clinical trials in this elderly population with the adenovirus as vector is going to get a decrease in efficiency. We're working at improving that efficiency.
"In our in vivo experiments," Hajjar went on, "we asked aging rats: Can we transduce your heart cells the same way as in adult rats?' And the answer was no.' The elderly rodent has a much lower efficiency. Our 26-month-old aging rat is like an 80-year-old human. Our rat experiments in the last year, as reported in Circulation, netted three results: 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 the biotech industry," Hajjar observed, "which is planning human gene therapy in the cardiac-disease world, a negative result from their studies may be due to this decreased efficiency, and not," he concluded, "because of the biology they're trying to alter."