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New virus offers gene therapy a boost
By Bijal P. Trivedi

Researchers have discovered a new virus that may prove invaluable for treating diseases with gene therapy. A preliminary round of results shows that the first disease that could be conquered is the genetic bleeding disorder, hemophilia B.

The goal of gene therapy is to treat disease by delivering a healthy gene to people whose copy has been lost or damaged, rather than by prescribing a drug. The advantage is that the gene becomes part of the chromosome and produces the missing protein. The challenge for gene therapy is delivering enough of the healthy gene to exert a therapeutic effect.

Now researchers have found that AAV1 (adeno-associated virus type 1) efficiently delivers therapeutic genes to more cells and produces significantly higher quantities of protein than AAV2, which is currently used in hemophilia trials. Using AAV2, researchers are able to produce less than one percent of the Factor IX clotting protein that is present in a healthy person; which may be enough protein to slightly reduce the severity of the disease, but is not enough to be considered a cure.

If the new results with AAV1 in mice translate to humans, there would be 20 times more Factor IX than a person needs, says Richard Samulski, of the University of North Carolina at Chapel Hill.

Samulski and his colleagues tested five types of virus—AAV1, AAV2, AAV3, AAV4, and AAV5—which are all similar except that the outer coat of these viruses varies slightly. The proteins on the outer coat are the keys to infecting cells; those on the surface of AAV2 only allow it to infect slow twitch muscle. To the researchers' surprise, AAV1 and AAV5 were able to infect and deliver genes to slow and to fast twitch muscle types. "The type 1 virus must have a master key for getting into muscle," says Samulski.

The shortcomings of AAV2 can be understood by talking about chicken. "There are two types of muscle—slow twitch and fast twitch," he explains. "Slow twitch muscle is the dark meat, it's the muscle you need for endurance. Fast twitch is the white meat that you need for short bursts of energy, like sprinting. AAV2 only infects slow twitch muscle, which is why its effectiveness can vary so much from one person to another, depending on the amount of each type of muscle."

When the researchers compared the amount of Factor IX clotting protein produced by each of the viruses, they found that mice receiving the gene from AAV1 produced up to a thousand times more protein than the mice that received the gene delivery from AAV2. In fact, all the other types of virus produced more protein than AAV2.

The North Carolina team will now focus on testing AAV1 in dogs. Obtaining similar results in a large animal will give the researchers more confidence in what to expect in humans. "If research in the dog produces similar results to those in mice then AAV1 has the hallmark of a cure," says Samulski. Human clinical trials could take place as early as 2002.

The researchers will also investigate which protein allows AAV1 access to both fast and slow twitch muscle. The answer could determine whether the virus could be directed at other organs like the brain, liver and kidney. Samulski is also hopeful that if AAV1 works well in dogs it may be used to treat other diseases simply by replacing the gene carried by the virus.

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Chao, H. et al. Several log increase in therapeutic transgene delivery by distinct adeno-associated viral serotype vectors. Mol Ther 6, 1-5 (December 2000).

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