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The gene therapy trial for Parkinson's disease uses a virus to carry the therapeutic genes into patients' brain cells. As this ScienCentral News video reports, in past gene therapy experiments, it is the viruses used that have been blamed for life-threatening side effects. 

Tragic Beginnings

Gene therapy has been heralded as a way to not only treat genetic diseases, but to cure them as well. But it has had some major safety setbacks in recent years. In 1999, 18-year-old Jesse Gelsinger died in a gene therapy trial for an inherited liver disease called ornithine transcarbamylase deficiency. And last year in France, two children who received gene therapy to treat the immune deficiency known as X-linked Severe Combined Immunodeficiency syndrome (XSCID), or "bubble boy disease," developed leukemia.

In both cases, experts blamed the tragic side effects on the viruses used by gene therapists as so-called "vectors" to carry the corrective genes into patients' body cells. 

"The vector is the vehicle for carrying the gene into the appropriate tissues in the body," explains Mark Kay, professor of pediatrics and genetics at Stanford University. "Viruses…normally carry their own genetic information into cells of the body. That's the process of how viruses make you sick. But what we as genetic therapists do is basically use the vehicle of the virus to carry therapeutic genetic information into cells rather than the viral genetic information."

In the case of the French children, the vector inserted itself next to a cancer-causing gene that became activated. "When it was activated, it contributed to the formation of leukemia in these children," says Kay. Up until the two boys developed symptoms of leukemia, the X-linked SCID trial was considered the most successful gene therapy trial ever.

Kay says the virus that is being used in the new Parkinson's trial, called adeno-associated virus, or AAV, is considered safer. "This virus naturally occurs in the environment, and most individuals have been infected with this virus, and it doesn't make you sick, it just is known to infect individuals."

But a mouse study in Kay's own lab looked at whether the AAV virus might also insert itself near or within genes where it could do harm. "What we learned was that when the AAV vector did integrate, although it integrated at a very low frequency, very, very rarely, when it did integrate, it did happen to integrate at high frequency into active genes. So this did raise the concern as to whether the AAV vector may have similar properties."

However, Kay, who uses AAV in his gene therapy work to treat hemophilia, and is on the scientific advisory board of Avigen, a biotech company involved in developing the therapy, says that because of the rarity of AAV integrating, and the many animal studies that have failed to find harmful effects, it should be used in gene therapies against life-threatening diseases. "There have been a large number of studies that have been done, and there have been safety meetings put on jointly by the FDA and the federal government sponsored by the NIH, in which a body of literature was assembled, and it was deemed at this point in time that there was no evidence to suggest that AAV had increased the risk of cancer in animals."

Scientists are now trying to come up with ways to control where the vectors insert into DNA. "Vectors now tend to just insert wherever they insert, all throughout the different chromosomes, all over the place, if you will," says Kay. "Think about it as a car just randomly bumping into a lot of other cars. It can hit any car that's in its path or on the road. But what scientists are attempting to do now is to control the insertion so that there's a very narrow range of where the DNA can actually insert itself, and by doing that, we can skew it away from inserting into detrimental regions of our DNA."

Kay is optimistic about the future of gene therapy. "There have been some unexpected technological hurdles that have come along the way, but all of these are solvable and I think it's just a matter of time…I think it's important to understand that gene therapy ultimately can be used to cure a number of different diseases."

This research appeared in the June, 2003 issue of Nature Genetics http://www.nature.com/ng/, and was funded by the National Heart, Lung and Blood Institute of the National Institutes of Health.
 

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