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Gene Therapy Makes Male Mice Fertile

Technique could one day help infertile men, researchers say

MONDAY, Jan. 28, 2002 (HealthDayNews) -- Japanese researchers have succeeded in bringing fertility to male mice with a genetic defect in cells that help sperm mature normally.

Scientists at Kyoto University used a virus to insert a corrective gene into abnormal Sertoli cells -- which normally support and nourish developing sperm -- in infertile male mice. The procedure restored enough fertility so the researchers could impregnate female mice with the males' sperm using in vitro fertilization (IVF), producing normal offspring.

The findings, which appear in the Feb. 5 issue of the Proceedings of the National Academy of Sciences, are the first to report the successful use of gene therapy to treat male infertility, says one expert.

The Japanese researchers carried out their experiment on mice with a genetic mutation that interferes with the production of a protein that provokes sperm maturation. Before sperm can fertilize an egg, it must mature – a process that takes roughly 35 days in mice and about 75 days in humans.

So far, there is no known direct equivalent of this mutation in humans, where defects in the cells that generate sperm are often responsible for male infertility. This condition is called Sertoli cell-only syndrome.

But senior investigator Dr. Takashi Shinohara suspects defects in human Sertoli cells that are linked to infertility will be discovered.

Shinohara, an assistant professor of medical chemistry, injected several copies of the virus carrying the corrective gene into the long tube in the mice testes containing Sertoli cells.

The virus delivered the gene into the cells, restoring partial sperm production. The animals still weren't fertile enough to reproduce naturally, with only 7.4 percent of the testes containing mature sperm. But that was enough mature sperm so the researchers could fertilize embryos using IVF.

"The actual percentages [of the testes containing mature sperm] are fairly low, but that's not surprising. This is a fairly new technique, and a lot of the efficiency details would have to be worked out," says Derek J. McLean, a research assistant professor of molecular biosciences at Washington State University.

The embryos were implanted into female mice, which produced healthy, fertile offspring.

None of the seven male and 13 female mice that were born showed any sign of the DNA [genetic material] from the virus, which is crucial, says McLean.

"If you do take this to a human clinical application, you want to avoid integration and transmission of [foreign] DNA [into sperm or egg DNA]," he says.

"That's obviously a risk, because it could be randomly inserted into [a person's genetic make-up]," he says. "That could potentially be harmful."

Shinohara agrees.

"People in the gene-therapy field have always had this concern about the … integration of the therapeutic virus," he says.

Still, McLean is optimistic these findings could ultimately be relevant to human infertility, perhaps even within five years, but only after the safety issues of gene therapy are addressed.

"This model of mice is very similar to the findings found in Sertoli cell-only syndrome in humans," says Shinohara. "There are no effective methods to cure those people, because they have almost no [sperm] cells."

"In these people, maybe we'll be able to restore fertility by transferring genes to their Sertoli cells," says Shinohara. But he stresses that it might restore only enough fertility to permit IVF.

Shinohara suspects the completion of the Human Genome Project will lead to the discovery of many other genes associated with infertility.

What To Do: For more information on Sertoli cells, check out the Virginia-Maryland Regional College of Veterinary Medicine. For general information on infertility, visit the American Society of Reproductive Medicine or IVF.com.

SOURCES: Interviews with Takashi Shinohara, M.D., Ph.D., assistant professor, Department of Medical Chemistry, Kyoto University, Kyoto, Japan; Derek J. McLean, Ph.D., research assistant professor, School of Molecular Biosciences, Washington State University, Pullman, Wash.; Feb. 5, 2002, Proceedings of the National Academy of Sciences
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