With Collaboration, Scientists Test Gene Therapy for 'Bubble Boy Disease'

A new variation of gene therapy raises hopes for a safe and effective long-term treatment for X-linked severe combined immunodeficiency syndrome (SCID-X1), a life-threatening heritable disorder.

The research was produced by a collaborative research team from Dana-Farber/Boston Children's Cancer and Blood Disorders Center, along with other institutions participating in an international clinical trial that involved boys from the United States and France.

SCID-X1, dubbed “bubble boy disease” after a patient who lived for 12 years in a sterile bubble, is a rare genetic disorder that hinders the ability of individuals to combat infections. Because the disease is carried in an X-chromosome recessive pattern, the disorder occurs almost only in males. The resulting mutations inactivate a gene called IL-2 receptor gamma (IL2RG), severely weakening immune system functions. Left untreated, individuals who inherit the disorder usually die within a year.

Previous gene therapy trials conducted in Europe over a decade ago promised dramatic progress, until a quarter of patients developed leukemia about two to five years following treatment. Scientists found that the previously used vector—the device for transporting the correct gene in therapy—inadvertently activated oncogenes, which can cause cancer.

In this new study, the vector in use is a self-inactivating gammaretrovirus, which has a “specific sequence deleted that basic research had implicated in the process of inappropriate activation of oncogenes,” David A. Williams, chief of the hematology/oncology department at Boston Children's Hospital, wrote in an email.

Of the nine patients who underwent the treatment, eight had survived between 12 and 38 months after treatment. One boy died from a severe infection he was fighting at the time he enrolled in the study.

A single round of therapy restored normal disease-fighting T cell count—300 cells or more per microliter of blood—in six of the eight patients. One patient underwent a second round of treatment and remains healthy despite a low cell count. The eighth patient received a hematopoietic stem cell transplant after the therapy led to “less than optimal uptake of the virus” and failed to stimulate T-cell production, according to Williams.

“We feel the ‘surrogate’ assays for safety look excellent and are very encouraged,” Williams said. “However, because leukemia can take years to develop (and although some of our patients are now approaching 4 years of [follow-up]) we must be cautious and continue to follow these children closely.”

Williams noted that the research was the result of positive collaboration between institutions.

“Work by Sung-Yun Pai and Gigi Notarangelo, funding from [Boston Children’s Hospital] (and other children’s hospitals) and [the National Institute of Health] were essential for success,” he said. “This is the first international collaborative trial in stem cell gene therapy, which was critical for success due [to the] rarity of [this] disease.”