Gene Therapy Homes In

Researchers have taken a step toward changing gene therapy from a blunderbuss into a smart missile. Most proposed gene therapies rely on viruses to carry desirable genes into cells, and because the virus indiscriminately infects all types of tissues, the gene appears even where it is not wanted. But by equipping a gene with a genetic "switch," a group at the University of Chicago was able to turn it on only in smooth muscle cells in experimental animals. The achievement could open the way to a genetic treatment against the growth of smooth muscle tissue that can block arteries in heart patients, and ultimately to other targeted gene therapies.

The lack of discrimination in the viruses used to carry therapeutic genes has been a major obstacle to testing gene therapy in humans. A gene that stopped cell proliferation, for example, could be potentially harmful if expressed in liver, lung, or other cells. But in the 1 September issue of the Journal of Clinical Investigation, cardiologist Michael Parmacek and his colleagues at the University of Chicago describe how they deleted two genes from the common cold virus to make it unable to cause any sniffling or fever, then replaced them with a marker gene that turns out an easily detected protein and the
SM22alpha promoter, which turns on expression of genes in smooth muscle cells that surround arteries. They injected this handcrafted virus into rats and found that the marker gene was indeed active only in smooth muscle cells. Liver and lung cells remained untouched.

If the SM22alpha promoter could be linked with a therapeutic gene, such as one that curbs the proliferation of smooth muscle cells in heart arteries that have been widened in a procedure called angioplasty, the medical benefits would be enormous. Nearly 30% of the 500,000 angioplasties performed every year in the United States lead to a second procedure after proliferating smooth muscle cells reblock the arteries. Hyperactivity of bronchial smooth muscle cells has also been implicated in asthma, so asthma patients might also benefit from gene therapy targeted to these cells.

"There is no single magic bullet that will solve all the problems associated with gene therapy," says Elizabeth Nabel, a cardiologist at the University of Michigan, Ann Arbor. "But this work does represent a major step forward. I believe this will go very rapidly to [large] animal testing and eventually human clinical trials."