Gene Therapy May Offer Treatment Options
For Patients Lacking Immune Systems

A new gene therapy method has turned the bone marrow of two young children from an "immune cell desert" into a healthy breeding ground for a variety of infection-fighting agents. The children have a form of severe combined immunodeficiency disorder (SCID) that typically requires patients to stay in sterile environments. They are now living and developing normally, Italian and Israeli researchers report in the journal Science, published by AAAS. Specifically, the two children have a form of the disease called ADA-SCID, in which they do not produce the ADA enzyme necessary for making immune cells. The disease can be controlled to a certain degree by regular injections of the bovine form of ADA, an expensive proposition in many countries. Approximately 30-50 infants with ADA-SCID are born each year, but only a small portion of them are diagnosed, according to study co-author Claudio Bordignon of the San Raffaele Telethon Institute for Gene Therapy and Università Vita-Salute San Raffaele, in Milan.

Shimon Slavin of Hadassah-Hebrew University Medical Center holds Salsabil, 22 months, who was born with severe combined immunodeficiency disorder, or SCID. Photo: Courtesy of Hadassah-Hebrew University Medical Center.

Bone marrow transplants have also been successful in some cases, but they pose serious risks of their own. There was no available donor for the two children in the study, who were seven months old, and two years and six months old.

"With gene therapy you can treat every patient, and the toxicity is enormously lower than for bone marrow transplants. We propose, at this stage, that every patient lacking a donor with an identical tissue type should be directed to gene therapy," said Bordignon.

Bordignon's team must test their therapy on more volunteers before it will be approved for researchers to use in Italy or abroad. They will start with patients without a matched donor for a bone marrow transplant, and may then include patients for whom a donor is available. Because ADA SCID is a relatively rare disorder, these studies would function as phase I and II clinical trials, meaning they aim to demonstrate that the procedure is both safe and effective, Bordignon said.

In order to extend this method to a larger population of Italian patients, the group is seeking the approval of Italy's Istituto Superiore de Sanità. A similar application process will be necessary for performing the therapy elsewhere in Europe and in the United States. According to Bordignon, because the therapy could considered under the "orphan drug" category—meaning a treatment for a rare disease—the approval process in Europe should be relatively fast, lasting only a few months.

Bordignon and his colleagues removed some of the bone marrow from the pelvises of the two patients in the study. Next, they isolated the blood stem cells, which have the potential to develop into the body's various red and white blood cells. When researchers exposed the stem cells to an engineered virus carrying a healthy version of the ADA gene, the virus inserted the gene into the stem cells' genome.

Before injecting the engineered stem cells into the patients, the Science authors performed an additional step, which they believe will make their efforts more successful than previous efforts to treat SCID with gene therapy. Until now, Bordignon says, these efforts have not established enough healthy stem cells in the body for the results to last. This time around, a process called "non-myeloblative conditioning" may make the difference, according to the researchers.

"Non-myeloblative condition means you don't really wipe out the bone marrow, you just give one of the drugs used in for a transplant, at a much lower dose, to make 'space' for engineered marrow to seize, expand and grow better," Bordignon explained.

Within weeks after being injected into the patient, the engineered stem cells migrated to the bone marrow and began spawning key types of immune cells, such as B cells, T cells and NK cells. Within months, antibodies appeared, and the patients responded normally to small amounts of certain pathogens, such as the tetanus vaccine. One year later, one of the patients no longer had the respiratory infections, chronic diarrhea or scabies that were common before the therapy.

Because the ADA enzyme is used for a variety of metabolic processes in the body, ADA-SCID is more complex than other diseases. In previous studies, Bordignon said, researchers had to continue giving patients enzyme replacement therapy for the metabolic problems, even when gene therapy had the immune component of the disorder under control.

The two patients in the Science study never received enzyme replacement therapy, which is not an option for them in their home countries. Bordignon's group observed the build-up of minimal amounts of toxic metabolites, indicating that the gene therapy was controlling the metabolic side of the disorder as well.

Eventually, Bordignon plans to attempt to use the gene therapy method for treating other diseases, including AIDS.

This study follows earlier research by Marina Cavazzana-Calvo and colleagues, published in the 28 April 2000 issue of Science. The French research team used blood stem cells in gene therapy to treat two infants with SCID X1, a variation of the disease caused by a mutation on the X chromosome.

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The other members of the research team are Alessandro Aiuti, Francesca Ficara, Sara Deola, Alessandra Mortellaro, Grazia Andolfi, Federica Cattaneo, Sergio Vai, and Maria Grazia Roncarolo, of the San Raffaele Telethon Institute for Gene Therapy, in Milan, Italy; Shimon Slavin, Memet Aker, and Shoshana Morecki, of Hadassah University Hospital, in Jerusalem, Israel; Antonella Tabucchi, Filippo Carlucci, and Enrico Marinello, at the University of Siena, in Siena, Italy; Paolo Servida, of Scientific Institute H.S. Raffaele, and Roberto Miniero, at the University of Turin, in Turin. Maria Grazia Roncarolo is also at Università Vita-Salute San Raffaele, in Milan, Italy. The study was funded by the Italian Telethon Foundation.

—Kathleen Wren

28 June 2002