A little girl named Salsabil is now 2 and a half years old, and healthy. Born to an Arab family in East Jerusalem, she owes her life to two gene therapy teams, one Israeli, the other Italian. Immunotherapist Shimon Slavin, director of the National Bone Marrow Transplant Center at Jerusalem's Hadassah University Hospital, tells Salsabil's tale:

"The family tried for a long time to have a baby," he recounted. "Finally, they gave birth to a boy. They were very happy until he died from ADA-SCID disease a few weeks after being born. But by the time the neonate was diagnosed with adenosine deaminase [ADA] and severe combined immunodeficiency disease [SCID], it was too late."

ADA-SCID, a rare - one in 100,000 - inherited absence of immune system cells, is popularly known as "bubble-baby disease," because its newborn victims must be shielded from infectious pathogens - bacteria, viruses, fungi, protozoan parasites and live vaccines. Its usual cause is absence of a functioning ada gene and the enzyme it encodes. In 1990-91, in Ohio, two small girls with ADA-SCID received infusions of ada genes, plus bovine PEG-ADA enzyme replacement.

"When the Jerusalem family became pregnant again," Slavin continued, "a girl [Tasmin] was born. We knew about the first child who died, so immediately we diagnosed this ADA-SCID deficiency - but there was no matched donor. So we did gene therapy the way it was done until that time. Despite ada infusions, the patient depended unavoidably on enzyme replacement.

"The mother became pregnant again, a third pregnancy," Slavin went on, "but she, a devout Muslim, refused prenatal diagnosis. So the moment the boy baby was born we cryopreserved his umbilical cord blood. Placental cord blood can serve as an abundant source of bone marrow stem cells. You can cure patients by the blood that comes out of the placenta. But that child, a boy, turned out normal - without ADA-SCID. So we administered a cord blood transplant to the second baby. [Tasmin's] now 3 and a half years old, and cured. Then the mother became pregnant again, and Salsabil was born in February 2000. She did not have a donor, and was the subject of our new-method gene transfer intervention."

Italian Gene Therapists Join Israelis In Jerusalem

Slavin is co-author of a report in the current issue of Science, dated June 28, 2002. Its title: "Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning." Its co-senior author is pioneer gene therapist Claudio Bordignon, at the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy. The paper's first author is gene therapist Alessandro Aiuti, also of Milan, and its second author, Slavin.

"We had worked for four years to develop the preclinical and clinical gene transfer protocol," Aiuti told BioWorld Today. "So we went to Jerusalem to perform the procedure on baby Salsabil, in collaboration with Shimon Slavin. We provided a retroviral vector to deliver a healthy ada gene to blood stem cells from the patient's bone marrow. And we did the follow-up immunological and molecular biological studies here in Milan."

"Salsabil - Patient 1' in the Science paper," Slavin observed, "is now completely cured without ever receiving an enzyme supplement. Consequently, this is the first example of a total cure of ADA-SCID by gene therapy alone because it's almost two years out. And interestingly, not all the cells are enzyme-producing genes. The patient also shows normal function of immune system B cells, T cells and natural killer cells positive for the gene. There is evidence that the stem cells themselves are genetically transduced, and consequently macrophages and neutrophils were also produced. And the best test for that," Slavin related, "is that Salsabil's family had an epidemic of chicken pox. Normally it's a very infectious disease, but Salsabil did not catch the chicken pox, and produced normal antibodies against that highly contagious infection.

"Our Italian collaborators," Slavin added, "six months after what we did in Jerusalem, treated another little girl - Patient 2' - from Colombia. And right now there's a third patient in Italy from Venezuela.

"We treated Patient 2 at 2 and one half years of age," Aiuti recounted. "She's now got normal weight and development, hasn't experienced any more infections. She has good immune function reconstitution, and is doing great 15 months after the therapy - living her life in her native country.

"We will certainly enroll more patients for ADA-SCID," Aiuti predicted, "and plan to extend it in Italy and Europe. We have an ongoing collaboration with Slavin, and will treat more patients together, while continuing to follow up our mutual Patient 1. It may be possible also to extend this approach to other genetic diseases involved in the hematopoetic system."

After Blood Dyscrasias, Genetic, Autoimmune Ills

Slavin enlarged on this broader vision: "The strategy can serve as a model to treat all genetic diseases where insertion of a gene into stem cells is the way to go. It could treat maladies like Gaucher's disease, Tay-Sachs, metachromatic leukodystrophy, Hurler's syndrome. All such enzyme-deficiency diseases are potentially curable by stem cell transplantation. I will be able to transplant your heart, your kidney, your liver, without any drugs to suppress immune rejection. The entire immune system develops from stem cells. And therefore, the secret of success is to accept stem cells. Then you know you can use T lymphocytes to kill the tumors. Not just hematopoetic blood malignancies but also genetic and autoimmune diseases. You can cure multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus.

"You put the stem cells of the donor into the patient," Slavin continued, "and then the donor's T cells will kill all the hematopoetic stem cells. So it will become a general principle for all organ transplants, because if you can successfully transplant stem cells from any organ donor - living, related or cadaver - if the stem cell is accepted, anything is accepted. You won't need to use any immunosuppressive treatments any more."

Slavin summed up: "In the midst of all the violence in Israel, the life of a bubble baby' from Jerusalem's Arab community has been saved by a new protocol developed by a team of Israeli and Italian doctors for the treatment of children born without immune systems. This lifesaving approach," he concluded, "has wide-ranging implications for the successful treatment of genetic diseases."