Gene therapy possible for Sly's syndrome.

Geneticists at Jackson Laboratory in Bar Harbor report using gene therapy to cure a rare, inherited metabolic disorder - known in humans as Sly's syndrome - in newborn and adult mice. The team, led by Edward H. Birkenmeier, has so far spliced normal copies of the gene for the enzyme betaglucuronidase into the bone marrow of hundreds of mice, reversing all signs of the disease.

The mice were born with mucopolysaccharidosis Type VII, a disfiguring and eventually fatal disease caused by mutations in the genes that code for beta-glucuronidase. The mutations prevent production of the enzyme, which is needed to rid cells of complex sugars called mucopolysaccharides. Without betaglucuronidase, toxic levels of the sugars accumulate in compartments called lysosomes, which are responsible for breaking down cellular wastes. The buildup causes stunted growth, as well as deformities of the skeletal and nervous systems.

People with Sly's syndrome usually have cardiac murmurs and mental retardation, and most die before 2 years of age. "Currently, there's no definitive treatment for the disorder," says its discoverer, William S. Sly of St. Louis University School of Medicine. Sly says he and Birkenmeier have been able to produce moderate quantities of beta-glucuronidase through genetic engineering, but have not yet convinced a drug or biotechnology company to develop the engineered enzyme, which has a limited market.

As long as the enzyme treatment remains unavailable, Sly says, "this disorder would be a candidate for human gene therapy." In the recent mouse experiment, the inserted gene produced only 2 to 5 percent of the normal enzyme level, but this was sufficient to cure the disease, Birkenmeier says.