Genetic therapy: just a nasal spray away?

Genetic therapy: Just a nasal spray away?

A genetic treatment for some inherited respiratory diseases could one day come packaged in the form of a nasal spray.

U.S. researchers, collaborating with two teams in France, have developed genetically engineered cold viruses that can serve as Trojan horses, carrying healthy genes into genetically defective lung cells. They now report using a tailor-made cold virus to insert a normal human gene into the lungs of rats.

Study director Ronald G. Crystal says he hopes eventually to treat patients with cystic fibrosis or other inherited lung problems by spraying the engineered virus into their nasal passages. "I have no doubt . . . that if we administered it to a human it would work," says Crystal, a pulmonary researchers at the National Heart, Lung and Blood Institute in Bethesda, Md.

His group has devised a way to insert copies of normal human genes into a disabled version of a large, cold-causing virus classified as an adenovirus. Adenoviruses target the lining of the lung, where they can cause diseases ranging from the common cold to pneumonia. Some are also used in human vaccines.

In their experiments, the researchers spliced a gene for human alpha 1-antitrypsin -- a protein deficient in some emphysema patients -- into adenoviruses that were incapable of reproducing to cause disease. They then squirted solutions containing the engineered virus into the lung passages of rats. Although these rats are as susceptible to colds as humans, the viruses inserted the human gene into the rat lung cells without causing disease.

By tagging cells from the rat lungs with radioactive pieces of human genetic material, the team confirmed that the cells took up the human gene. They also detected human alpha 1-antitrypsin in the rats' lung secretations, using antibodies that would bind to human, but not rat, proteins.

In the April 19 SCIENCE, the researchers report that they found evidence of the human alpha 1-antitrypsin gene in the rat lungs for up to one week after administering in the solution. Crystal told SCIENCE NEWS that they have continued the experiments and can still find the gene after six weeks. "We haven't seen it go away," he says.

Despite these successful results, Crystal predicts that emphysema caused by alpha 1-antitrypsin deficiency will probably not be the first human disease treated by nasally administered gene therapy, since the disease is already treatable by other means. In 1987, researchers in his laboratory showed that alpha 1-antitrypsin isolated from donated human blood plasma was effective in treating emphysema. A growing number of the roughly 30,000 U.S. patients with alpha 1-antitrypsin deficiency now receive plasma-derived protein, although the therapy costs each patient between $30,000 and $40,000 a year, Crystal says.

He has set his sights instead on cystic fibrosis, one of the most common incurable genetic diseases. Cystic fibrosis causes a buildup of sticky mucus in the lungs and other organs, which leaves patients vulnerable to life-threatening infections. Crystal's group has begun animal experiments with adenoviruses containing normal copies of the defective gene that causes cystic fibrosis. The results "look promising," he told SCIENCE NEWS, but he declined to say how soon he will seek approval to test the therapy on human patients.

Michael J. Welsh, a cystic fibrosis researcher at the University of Iowa in Iowa City, says the new work "may turn out to be an important step along the way for treating various lung diseases." Welsh led one of the two independent teams that corrected the genetic defect in lab-cultured cells from a cystic fibrosis patient last year (SN: 9/22/90, p. 181).

"A very important question will be the safety [of the treatment]," Welsh adds. He cautions that patients could develop allergic reactions to the engineered adenoviruses, especially if the viruses must be administered repeatedly for life.