Health officials and clinicians have suspended gene therapy trials for Severe Combined Immune Deficiency (SCID) in the United States, France, and Germany following observation of a leukemia-like disorder in one patient who underwent the treatment. Recently hailed as gene therapy's first real success, the therapy had restored immune function to at least 14 children with X-linked SCID, the so-called "bubble boy" disease.

Alain Fischer at Necker Children's Hospital in Paris observed elevated T-lymphocyte levels initially thought to be associated with a chicken pox infection. The levels continued to rise after the infection subsided, and in September, Fischer contacted colleagues and health officials.

Christof von Kalle and colleagues at Cincinnati Children's Hospital are now trying to determine whether the condition, which Fischer calls lympho-proliferation, is caused solely by the insertion of the "therapeutic" gene into an inappropriate place in the genome. Cancer-causing insertions have long been a concern of those pursuing gene therapy. "This is a theoretical possibility that was known for some time," said Savio Woo, past president of the American Society for Gene Therapy, but such complications have never been seen before in human or animal studies.

Fischer's ex vivo technique uses a retroviral vector to transduce pluripotent stem cells from a sample of the patient's bone marrow, with a normal copy of the gamma c gene. The cells are returned to the patient and can begin producing immune cells that express the gamma c polypeptide. In the case of this boy, T-lymphocyte production has gone out of control, and he must now undergo chemotherapy.

Christof von Kalle has been working with Fischer for more than two years to determine which of the patients' cells have been transduced with gamma c. Using a PCR-based technique, he can also assess the exact insertion point. Preliminary results with this patient show that a therapeutic gene has been inserted adjacent to LMO2, an oncogene frequently activated in T-lymphocytic leukemias. But the unfortunate insertion point does not necessarily tell the whole story said von Kalle. "There is a hint of another genetic event in that cell clone because usually the activation of that oncogene alone is not sufficient," he told The Scientist. Other factors could include a viral infection or a genetic predisposition for cancer.

Though most agree that halting trials is the correct action, some also believe that the benefits of gene therapy may still outweigh the risks. Clinical trials are set to continue without changes in the United Kingdom said Adrian Thrasher, a pediatric immunologist at Great Ormond Street Hospital where four infants have been successfully treated. The alternative to gene therapy, allogeneic bone marrow transplant, has proven effective yet, in half-matched transplants, the mortality rate is 20% in the first year. According to Thrasher, patients' families are counseled about risks and the technique has proven beneficial so far.

The US Food and Drug Administration's Center for Biologics Evaluation and Research (CBER) has organized an emergency session for October 10, where safety issues and the current clinical hold on three SCID gene therapy trials in the US will be discussed. The side-effects pose a new challenge for the field, said Woo. "It's not a matter of 'does [gene therapy] work or not,' it's a matter of how do we make it work better."

Thrasher offered perspective, "We're at the beginning of a steep learning curve. For any radical change in medicine — from organ transplant to bone marrow transplantation — to start with, the results weren't as good as they are now."