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Gene Therapy Virus Linked to Genetic Changes

Expert doubts finding will pose problem for future of gene therapy

MONDAY, Jan. 21, 2002 (HealthDayNews) -- A virus that scientists commonly use to transport genetic material into damaged or defective cells during gene therapy may be linked to the deletion of genetic material in those cells, new research says.

A study by researchers at the University of Washington found that when the virus -- known as adeno-associated virus, or AAV -- was introduced into a collection of cancer cells in a laboratory study, parts of chromosomes in the cells were deleted and other genetic changes occurred.

The researchers say their findings may indicate that similar changes could occur in genetic material during gene therapy trials now being conducted on humans. But, they add, they don't think the genetic changes pose a health risk to patients.

However, a genetics experts not associated with the study cautions that, because the findings are preliminary, the effect on human genetic therapy is not yet clear.

The study, which appears in tomorrow's issue of the journal Nature Genetics, became possible after the recent completion of the Human Genome Project, says senior investigator Dr. David Russell, a professor of medicine at the University of Washington in Seattle.

Once the human genome sequence was available, says Russell, researchers were able to re-examine existing data on how the AAV virus interacted with the cells targeted by gene therapy.

Russell and his colleagues introduced the AAV virus into a line of cancer cells, then examined the DNA -- or genetic material -- of the virus and the cancer cells' chromosomes.

"The DNA from the AAV [virus] integrates into the chromosome," says Russell.

Once the AAV virus had integrated with the chromosome of the cells, the researchers examined the DNA from the cancer cells. They were searching for the points at which the genetic material in the virus linked with the cancer cells' DNA.

"Most of the time, the [virus] integrates, and at the point of integration [roughly] 10 to 70 base pairs of chromosomal sequence are deleted, and the [virus] is inserted in that position," says Russell.

But Russell says that this finding shouldn't sway researchers from using the AAV virus in gene therapy.

"We knew AAV integrated already," he says. "Just putting the [virus' genetic material] into the chromosome is going to disrupt whatever gene you integrate into."

"The fact that it deletes 10 to 70 base pairs at the same time is a very minor consequence, compared to the whole effect of putting a [virus' genetic material] in," he adds.

"I don't think it really changes our impression of how safe these [viruses] are," says Russell. "This is really [research] that gets closer to the mechanism and figures out exactly what's going on."

Previous research has suggested that the AAV virus is more likely to integrate wherever existing chromosomal damage exists. But there is no evidence that the AAV is causing the damage. Russell points out that billions of people have been naturally exposed to the adeno-associated virus without developing disease.

However, Dr. Mark Kay, a Stanford University professor of pediatrics and genetics who is familiar with the study, points out that this research didn't look at a real-world situation.

"These studies were done in a cancer cell line that's already genetically messed up," he says, explaining that the cell line already had damaged chromosomes due to the cancer.

"How this would extrapolate to normal tissues and normal situations is really hard to [say]," he adds.

But even if the same process occurs in non-cancerous cell targeted for gene therapy, Kay doubts it would pose a problem for those cells.

"AAV as a vector is very inefficient at integrating into the chromosome," he says. "In rodent models -- in normal rodent liver and tissues -- there's very little of the [AAV] DNA actually integrated."

Kay says that although public concern over the safety of gene therapy has been heightened by some highly publicized failures, including the death of 18-year-old Jesse Gelsinger in a University of Pennsylvania gene therapy study, these findings shouldn't affect the use of AAV as a vector for gene therapy.

"There's a heightened awareness," says Kay. "There is an emotional component to the response because of what's happened."

And he adds, "I don't think too many conclusions about a real-life situation where you would use these vectors can be extrapolated yet from this study."

However, he says, it represents a starting point for other avenues of research.

What to Do: For more information on gene therapy, check out Indiana-Purdue University, this article from Scientific American, or the Institute for Human Gene Therapy.

SOURCES: Interviews with David W. Russell M.D., Ph.D., professor, department of medicine, University of Washington, Seattle; Mark A. Kay, M.D., Ph.D., professor, departments of pediatrics and genetics, Stanford University, Palo Alto, Calif.; Jan. 22 Nature Genetics
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