An experiment designed to treat Sly syndrome, one of theworld's rarest inherited diseases, reportedly resulted in "thefirst example of hereditary illness reversal by gene therapyalone."

The reversal prolonged the life, and improved the well-being,of three mice afflicted with Sly syndrome, a liposomal storagedisease also known as mucopolysaccharidosis type VII (MPSVII).

Although in vivo expression of the gene, transferred to targetsomatic cells, was unexpectedly low, its metabolic activity inmitigating the ravages of MPS VII was surprisingly high.

The report of the paradoxical experiment appears in Nature'send-of-year double issue, dated Dec. 24/31. The lead author ofthe article is molecular geneticist John H. Wolfe, whoinvestigates the disease in a breeding colony of mutant dogsand mice, animal models for human MPS VII, at the Universityof Pennsylvania's National Referral Center for Large-AnimalGenetic Diseases in Philadelphia.

There are only about 50 known cases of human MPS VII in theworld, said William S. Sly, who reported the first case in 1973,and after whom the syndrome is named. Sly, who is chairmanof biochemistry and molecular biology at St. Louis UniversitySchool of Medicine, told BioWorld that MPS VII isunderdiagnosed, "perhaps not more than twofold."

Its cause, he explained, is a mutant gene on humanchromosome 7, which prevents expression of b-glucuronidase.This is an enzyme that normally prevents accumulation ofmucopolysaccharide, a complex sugar essential to cellmetabolism. Absence of the enzyme causes the sugars, notablyglycosaminoglycan (GAG), to build up, starting a few monthsafter birth to the end of a much-shortened life span.

It damages a large number of organs, from liver, spleen, lungs,kidneys and thymus to cornea, brain and bone.

"MPS VII is inherited as an autosomal recessive trait, likecystic fibrosis," said Sly. "It's just that the number of peoplecarrying the deleterious gene is much smaller."

Unlike cystic fibrosis, most prevalent in Caucasians, or Tay-Sachs disease, with Ashkenazi Jews, Sly syndrome is notidentified with any specific population. Sly's founder casehappened to be a 6-week-old black baby brought to hishospital in 1969 with club feet. His facial features suggested anunusual condition, and led to biochemical analyses, whichconfirmed that the child suffered from a form ofmucopolysaccharidosis, but unlike the six other forms thenknown and numbered. He died about two years ago at age 20 .

Wolfe and his associates inoculated eight adult MPS VII micewith some of their own bone marrow stem cells infected withhealthy b-glucuronidase mouse genes packaged in a retroviralvector. First, they irradiated the animals to knock out the restof their bone marrow.

They found evidence of enzyme activity in 26 percent of onetypical mouse's bone marrow, but only 6 percent in spleen andlymph nodes, and 2 percent or less in thymus, kidney, liverand lung. Yet, as Wolfe told BioWorld, the grossly swollenlysosomes of liver and spleen cells showed reduction of theirGAG burden of storage sugars, and the mice seemed friskierthan their untreated control mutants.

"Our results," Wolfe said, "indicate that the amount offunctional enzyme that can be delivered, even though it ismuch lower than normal, may still be of value to patients withany of the mucopolysaccharidosis diseases."

He now intends to scale up the gene therapy from mice to dogs.

What about simply supplying human MPS VII patients withmaintenance doses of the enzyme they lack, much as diabetespatients take replacement insulin?

"The question is," Wolfe replies, "can we make enough of thestuff to treat a human patient? We'd have to keep supplying itchronically."

At St. Louis University, Sly synthesizes recombinant b-glucuronidase in Chinese hamster ovary host cells, using amethotrexate gene amplification system. He gets enough onlyfor mouse-scale experimentation. "We would be interested inproviding the enzyme to patients," he told BioWorld, "but wecan't find any company that's willing to undertake it becausethe human MPS VII population is so small."

Sly adds wryly, "We can produce 10 milligrams per liter of therecombinant enzyme in cultured cells, which we know iscorrective for these patients. But then we're out of business.We can't get to the next step and find someone willing toundertake the production."

Ruefully, he muses, "I never patented it; probably I shouldhave. It's becoming something a lot of people are interested in."

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.