Breathe easy. Rabbits with fewer receptors for adenosine suffer less from asthma. Antisense DNA can reduce the production of the A1 adenosine receptor, whose molecular structure (shown above) is published here for the first time.

Making Antisense of Asthma

In a potentially lethal overreaction of the immune system, something as seemingly harmless as dust mites or pollen can leave a person with asthma gasping for air. Drugs provide some relief from these attacks, but more help may be on the way: In tomorrow's issue of Nature, researchers describe a key biochemical signal involved in asthma and show how a snippet of DNA may prevent an attack.

Asthmatics have trouble breathing in part because muscles constrict airways throughout the lungs. A suspected trigger for this constriction is adenosine, a chemical messenger found in high amounts in the lung fluid of asthmatics, says Jonathan Nyce, a molecular pharmacologist at EpiGenesis Pharmaceuticals in Greenville, North Carolina. Nyce and his colleague James Metzger, a clinician at East Carolina University, have devised a way to reduce the sensitivity of lung cells to adenosine by interfering with the production of cell receptors that bind it.

Nyce's group created a single strand of DNA whose amino acids complement those in the messenger RNA that helps make adenosine receptors. The idea is that adding this "antisense" DNA to lung cells should tie up the mRNA, preventing it from doing its job. "The beauty of this approach is that you can create a drug that interferes only with your target," says Nyce. Using a computer to model the mRNA's structure, Nyce and Metzger made antisense DNA just 21 bases long--a fraction of the 3000-base mRNA--that interferes with a critical loop in the mRNA.

The crucial step, though, is to get the antisense DNA into the target cells. Antisense therapies for cancer, for example, have had trouble delivering high enough concentrations of DNA to tumors, says Nyce. Treating lungs has several advantages. The tissue is easily reached with sprays and has tremendous surface area for absorbing drugs. A slippery liquid that coats the cells also attracts and packages the antisense DNA, thus providing an entrance when the fluid is recycled by the cells.

Nyce and Metzger sprayed the antisense DNA into the lungs of eight asthmatic rabbits, the standard model for human asthma. The number of adenosine receptors dropped to normal levels, without apparent side effects, and asthma attacks were completely prevented for 12 hours. Animals treated with a control--antisense DNA just a few bases different--had three times as many receptors and suffered from asthma attacks. In addition, when the researchers tried to trigger attacks with dust mites and the inflammatory chemical histamine (thought to be released in response to the mites), rabbits treated with antisense DNA were insensitive. "That was quite startling," says Nyce, who plans to start clinical trials later this year.

Other experts find the results encouraging. "It's a good start," says pharmacologist Peter Richardson of Cambridge University, "and it should spur a lot more work." But he adds that much remains to learned. It's uncertain whether other cell types, such as the immune cells that enter the lungs after an attack, have adenosine receptors--and scientists don't even know the source of the adenosine.