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DNA Therapy Works Better Under Pressure

A high-pressure solution can dramatically improve the delivery of therapeutic DNA into cells, without the need for carrier viruses. The finding, reported in tomorrow's Proceedings of the National Academy of Sciences, could help improve the likelihood of success of cardiovascular transplants and other operations.

One type of gene therapy, called antisense therapy, aims to interfere with the unwanted expression of certain genes. Base by base, scientists build a short strand of DNA that exactly matches part of the gene's DNA sequence. Inside a cell, this antisense sequence binds to and inactivates the gene's messenger RNA, which normally would direct cellular machinery to produce the corresponding protein. Cardiologists, among them surgeon Michael Mann and his colleagues at Harvard Medical School in Boston, have shown that using antisense DNA to block genes linked to transplant rejection and disease can significantly improve the success of surgery in lab animals. The challenge has been devising a way to bypass the immune system and cellular defenses and deliver foreign DNA to the right cells.

One favored technique for delivering foreign DNA into cells is to use a modified virus as the messenger. Mann and his team took a different tack. They removed more than 100 hearts from rats and filled the heart chambers and blood vessels with a saline solution containing an antisense sequence designed to block a gene for an inflammatory protein. After bathing the hearts for 30 minutes at pressures of up to 2 atmospheres, they transplanted the hearts back into rats. Three days later, they found that half the heart cell nuclei had taken up the antisense DNA. Delivery rates with other techniques, including modified viruses, have rarely exceeded 30%.

When the researchers tried this high-pressure infusion technique on human leg veins, 90% of cell nuclei took up antisense DNA, and the production of inflammatory proteins plummeted. Researchers are still not sure why the method works, but it may simply involve more efficient diffusion and, perhaps, pressure-induced changes in the cell and nuclear membranes.

The results impress gene therapy experts. "I think it's great," says Gary Nabel, director of the Vaccine Research Center at the National Institutes of Health, who has worked on cardiovascular gene therapy. The technique is particularly attractive, he says, because "it can be simplified and put into practice in the operating room," where surgeons could manipulate transplant tissues as needed. Nabel also believes that high-pressure solutions could be adapted for use in gene therapies that deliver replacement genes to cells, perhaps even without removing tissues from the body.