Vanderbilt University Medical Center
Vantage: Gene Therapy
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"Inhale this drug twice a month" could become a prescription for fighting some of today's most dreaded ailments.

Inserting a therapeutic gene in human cells to fight cystic fibrosis, emphysema and other lung disorders may one day be as simple as breathing a medicated mist. Moreover, a form of gene therapy under research at Vanderbilt University Medical Center could, if successful, apply to thousands of illnesses, including cancer and AIDS.

"Even if a fraction of the possibilities work, it's going to be the major therapeutic advance in the next decade of two," predicts Kenneth L. Brigham, M.D., director of the Center for Lung Research and Joe and Morris Werthan Professor of Investigative Medicine at Vanderbilt.

In 1989, Dr. Brigham pioneered a procedure that successfully placed foreign genes in cells lining the lungs of mice. A more recent Vanderbilt experiment showed there genes will boost an animal's response to illness. Now Dr. Brigham and his associate, Jon T. Conary, Ph.D., await Food and Drug Administration approval to begin human trials.

The therapy hinges on the instrumental role of genes in regulating health. Genes are located on strands of DNA, the inherited material that forms the chromosomes found in each cell of the body. Every gene has a code, and these codes ultimately control virtually every body function, from growth to digestion. Consequently, a defective gene may result in a minor or serious illness.

Vanderbilt scientists are exploring a novel route for the delivery of the gene therapy. Many researchers hook a healthy gene to a piece of virus. the virus invades the cell and deposits the gene inside the chromosome. Vanderbilt is taking "an easier and probably safer" approach, says Dr. Brigham.

His Vanderbilt team grows circular portions of DNA, called plasmids. A therapeutic gene is placed aboard each plasmid, line a passenger on a rocket ship. Launched in a fine mist, the plasmid enters the windpipe and lungs. To enable it to land within cells, each plasmid is coated with liposomes - tiny globules of fat that permeate cell walls, carrying the plasmid with it.

Once inside the cell, the plasmid and the healthy gene aboard it act not as invaders but as helpful guests. They remain inside the cell nucleus but outside the chromosome, where the guest gene begins assembling the needed protein to improve health.

"Our goal is not to alter any indigenous genes," says Dr. Brigham. "The DNA we introduce doesn't integrate into the host gene, doesn't replicate in the body and works transiently , disappearing after several weeks." This approach eliminates the risk of damage from permanently inserting a gene at the wrong site on a chromosome or from activating the body's immune response system, as viruses will.

The Vanderbilt model of gene therapy has broad applications. For patients with a genetic-based illness, like cystic fibrosis, a gene could be introduced that offsets the effects of the defective gene. While not cured, the patient could be treated effectively by periodically inhaling the gene-containing spray.

For a patient with an acute, non-genetic illness such as adult respiratory distress syndrome, the gene could boost the body's ability to fight the bacterial infection that causes the often fatal condition. When no longer needed, the therapy would be stopped, and the gene would be naturally flushed from the body. For illnesses not confined to the lungs, the gene therapy would be administered intravenously instead of by aerosol.

The research must clear two major hurdles: human studies must show enough of the gene can be delivered to be effective, and patients must remain free of unacceptable side effects. At least five years of human trials are required before these answers will be in, says Dr Brigham.

Yet he is surprised by the swift progress to date and excited by the potential the therapy holds. "I never dreamed we would be anywhere as close as we are now to developing a whole new category of drugs," he says.

Copyright © 1996, Informatics Center, Vanderbilt University Medical Center

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