Gene Therapy For Anemia Succeeds In Animal Model

October 01, 1996

By directly injecting custom-built genes into muscle tissue in mice, researchers at the University of Chicago Medical Center have been able to produce long-term expression of the gene, continuous presence of the gene product in the circulation, and a lasting therapeutic response.

This is the first demonstration that an injected gene, without a viral delivery system, could produce and secrete enough protein into the bloodstream to make a clinical difference, and keep doing it indefinitely.

If this technique works as well in human trials, expected to begin next year, it could drastically decrease the need for erythropoietin, a drug used to treat certain types of anemia which are common in patients with kidney failure.

With an annual cost of nearly $8,000 each for more than 100,000 patients in the United States alone, sales of erythropoietin approached a billion dollars last year.

This innovative approach, reported in the October 1, 1996, issue of the Proceedings of the National Academy of Sciences, suggests that this method could be used not only to treat anemias that respond to erythropoietin, the hormone that stimulates the production of red blood cells, but also other disorders that result from too little secretion of a particular hormone into the bloodstream, diseases such as hemophilia and ultimately diabetes.

"Our results suggest that intramuscular injection of currently available genes could be used to treat a variety of serum protein deficiency diseases," said Jeffrey Leiden, M.D., Ph.D., professor of medicine, section chief of cardiology at the University of Chicago, and director of the study. "Gene therapy with a single shot would be much more convenient and far less expensive than the multiple weekly injections patients now require."

The "naked DNA" approach has several advantages over using viruses to ferry genes into muscle cells. Naked DNA is easier and less expensive to prepare. It reduces the risks of contamination. It eliminates the risk of DNA damage associated with some viral vectors. And it does not trigger the immune response that has prevented long-lasting expression of some virally transported genes, which tend to be eliminated within two to four weeks.

This report also gives credence to a recent rebirth of enthusiasm for gene therapy. Despite its initial luster, disappointing results from some early clinical trials tarnished the image of this emerging field.

As scientists have learned more about the potential and pitfalls of gene therapy, the field has gradually shifted away from these initially unsuccessful attempts to correct single-gene disorders such as cystic fibrosis and toward the simpler goal of inserting genes to serve as miniature pharmacies, producing and secreting recombinant proteins such as erythropoietin, clotting factors or insulin into the blood.

Erythropoietin-deficient anemias may prove the easiest target. Erythropoietin, produced in the kidneys, signals the bone marrow to produce red blood cells. But about 140,000 people in the United States produce too little of the hormone. These patients, who suffer from kidney failure or who take AZT for HIV infection, require two-to-three injections of recombinant erythropoietin each week, at a cost of about $8,000 per year. Gene therapy could replace these repeated treatments with a single injection.

By injecting as little as 10 micrograms (10 millionths of a gram) of the customized erythropoietin gene injected directly into muscle Leiden and coworkers produced a 25 percent increase in red blood cells in normal mice that lasted for the duration of the experiment, three months or longer.

Five years ago, no one considered muscle cells as a target for this type of gene therapy. In 1991, however, groups led by Leiden and by Helen Blau at Stanford demonstrated that muscle cells present an ideal target for gene therapy because they readily take up new genes and secrete the products of those genes into the bloodstream.

This report extends that finding by demonstrating a simple and long-lasting way to introduce new genes into muscle cells.

In addition to Leiden, authors of this paper include Eugene Goldwasser, Ph.D., professor of biochemistry and molecular biology, who first isolated erythropoietin in 1977, Sandeep Tripathy, Eric Svensson and Hugh Black, from the University of Chicago and Peter Hobbit and Michael Margalith from Vical, Inc.

This work was supported by grants from the National Institutes of Health, the Falk Foundation, and a gift of human erythropoietin DNA from Amgen Inc.

University of Chicago Medical Center

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