Adenosine deaminase deficiency

Sneaking in a therapeutic enzyme

The body's normal functions can work at cross purposes to a person's survival. Such is the case when the enzyme adenosine deaminase (ADA) is injected into babies born without the gene that produces it. The vital enzyme is quickly broken down, either by a knee-jerk immune system reaction to the foreign protein or by normal metabolic processes. Without ADA, the infants' immune systems eventually and fatally shut down.

So far, all attempts to directly replace the enzyme ultimately have failed, bone marrow transplantation of cells that make ADA is frequently not possible or successful, and gene therapy has yet to be used in humans.

Last month, researchers tried a new approach on an ADA-deficient infant using ADA studded with innocuous molecules that shield it from short-term destruction without disturbing the enzyme's active site. The treatment, claims Enzon, Inc., the South Plainfield, N.J., company that manufactures the altered enzyme, is simpler and safer than gene therapy.

Rebecca Buckley of Duke University in Durham, N.C., who is directing the human trial, says it is much too early to determine whether the treatment is effective. The patient had already received two bone marrow transplants, both of which failed.

ADA deficiency is one cause of severe combined immunodeficiency disease (SCID), sometimes known as the "bubble boy' disease, named for the Texas boy who lived most of his life in a sterile bubble. He died at age 12 after a bone marrow transplant (SN: 3/3/84, p. 133).

Bone marrow transplantation to graft in new cells that produce the enzyme is the only proven treatment for the rare condition. But a matched donor is needed, and the therapy fails about as often as it succeeds.

Research in gene therapy--transferring ADA-producing genes into the patient's own marrow cells--is currently under investigation at Memorial Sloan-Kettering Cancer Center, the National Institutes of Health and Princeton University (SN: 8/24/85, p. 117). Researchers at the three institutions have used a virus to transfer the normal human gene for ADA into monkey marrow cells, transplanted the cells back into the monkeys, and detected a low but significant level of human ADA production, Richard O'Reilly of Sloan-Kettering in New York City told SCIENCE NEWS. In addition to getting government approval, many details have to be worked out before the procedure can be used therapeutically, he says.

In the new enzyme-replacement technique, polyethylene glycol (PEG) is hooked onto the ADA. The PEG "studs' effectively block out the large immune cells while the small molecules on which the enzyme acts can slip through to the active site, explains Abraham Abuchowski of Enzon.

Normally, the enzyme conducts its business within blood cells--adenosine from the blood plasma enters the cells and is broken down by intracellular ADA. With the protected PEG-ADA, the interaction is in the plasma. "It's totally unnecessary to get the enzyme into the cell,' Abuchowski says.

Another PEG-coated enzyme is currently under evaluation in the United States and Europe for its activity against several types of leukemia. PEG-enzymes may also prove useful for some of the thousands of genetic diseases, Abuchowski says.

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