International Gene Therapy Trial Launched at Children's Hospital Boston for "Bubble Boy" Syndrome

July 07, 2010

Family Tree
Safer delivery vehicles could advance gene therapy for many genetic diseases

Boston, Mass. -- A new gene therapy trial for X-linked severe combined immunodeficiency (SCID-X1), the disease popularly known as "bubble boy syndrome," is now accepting patients. The international trial, one of several gene therapy trials being developed at Children's Hospital Boston, is the first to be given the green light by the FDA for SCID-X1 since 2005, since five children developed leukemia after being treated in Paris and London.

The previous trials demonstrated gene therapy's life-saving potential but also clearly indicated the need for improved safety. Based on careful analysis of these patients, the vector that delivers the critical gene, a retrovirus, was completely redesigned and the likely cancer-causing elements eliminated.


Click to see more information about blood after gene transfer.

"A number of in vitro studies and animal studies have clearly demonstrated the superiority of the new vector, says Luigi Notarangelo, MD, who directs research on primary immunodeficiencies at Children's Hospital Boston and is principal investigator of the study. "We and our collaborators expect it to be much safer."

The new vector and FDA-approved treatment plan were developed by the Transatlantic Gene Therapy Consortium, including Children's researchers, with major contributions from collaborators at the Hannover Medical School (Germany) and the Institute of Child Health in London. The trial underwent extensive regulatory review at the local, national and international levels.

The international, multicenter study will be sponsored in the United States by David Williams, MD, Chief of Hematology/Oncology and Director of Translational Research at Children's. It will seek to enroll a total of 20 patients with SCID-X1, a rare and frequently fatal disorder.

"This is a major step that utilized the adverse events of the initial gene therapy trials in Europe to go back into the laboratory in a highly collaborative manner and develop what we believe is a much improved gene delivery vector," says Williams, sponsor of the trial for all US sites.

The most common form of bubble boy syndrome, SCID-X1, strikes boys and, shortly after birth, renders them unable to fight germs. Without intervention, most children die at less than one year of age from bacterial or viral infections.

SCID-X1 is best cured by bone marrow transplantation from a brother or sister who is a bone marrow match. However, most patients do not have a matched donor in the family, and finding an unrelated matched donor can be prohibitively time-consuming.

"SCID-X1 is a life threatening condition," explains Notarangelo. "Providing treatment in a timely manner is essential to avoid otherwise fatal infections early in life."

Patients can also be treated by a bone marrow transplant from a partially matched donor (typically, a parent), but most often remain incapable of producing antibodies against infections, and thus require immunoglobulin infusions for life. Giving chemotherapy to eliminate the "wrong" cells in the bone marrow before transplantation may circumvent this problem, but this exposes infants with SCID-X1 to significant toxic side effects.

Furthermore, with any transplant, there is a risk of graft-versus-host disease, in which the donated cells launch an attack on the infant that can be fatal.

"The main advantage of gene therapy is that patients would receive their own cells, so there is no chance of graft-versus-host disease," explains Sung-Yun Pai MD, in the Division of Hematology/Oncology at Children's Hospital Boston, and a co-investigator on the study. "There is also no time delay in finding a donor and no need for chemotherapy."

During the trial, patients will be infused with stem cells isolated from their own bone marrow, in which a functional form of the gene mutated in the disease is introduced. The promoter used to turn on the replacement gene is believed to be a lot safer than the promoter used previously, because it should allow production of the missing protein at lower, more physiological levels, without inducing expression of other, unwanted genes.

The international research team believes that the gene therapy approach may also be effective in restoring immune function without chemotherapy. This is because only those bone marrow stem cells that are genetically corrected will be capable of developing into T lymphocytes, the critical immune cells missing in patients with SCID-X1, and perhaps will also mature into antibody-secreting cells, thus eliminating the need for life-long administration of immunoglobulins.

Six months after this one-time treatment, the children's immune systems will be checked to see if they are indeed in working order. Patients will then be thoroughly monitored for another 14.5 years, the length of time considered to be adequate to rule out the risk of cancer developing as a result of the treatment.

"There is a strong emphasis on safety," says Notarangelo. "We will monitor these patients very, very carefully."

The trial is open only to children who lack a readily available matched bone-marrow donor and who are above 3.5 months of age or are severely ill and unlikely to have a good outcome from a bone-marrow transplant. One half of the patients will be enrolled in the U.S.

The trials' other participating centers include Hôpital Necker (Paris), Great Ormond Street Hospital (London), Cincinnati Children's Hospital and UCLA School of Medicine. This is the largest multi-institutional collaborative effort to treat SCID-X1 with the same gene delivery vehicle, allowing the best evaluation to date of the gene therapy's efficacy.

The Transatlantic Gene Therapy Consortium was founded 7 years ago by David Williams, MDAdrian Thrasher, MD, PhD, of the Institute for Child Health and Great Ormond Street Hospital for Children in London; and Christopher Baum, MD, of Hannover Medical School in Germany to combat the leukemia that resulted in previous clinical trials of gene therapy. Participants have worked together to develop and test newer and safer vectors and share the cost of development of this and future clinical trials.

"It is a model for international collaboration for rare diseases," says Pai. "With rare diseases, you cannot make progress without collaborating."

The lessons learned are expected to pave the way for treatment of several other life-threatening single-gene diseases. Investigators at Children's, with their collaborators, are planning gene-therapy trials for several other rare diseases.

"It is clear that the many years of research investment and development are now paying off," says Williams. "We believe that continued investment in basic and translational research - specifically using this technology -- will lead to additional advances, bringing new therapies to children worldwide."

For more on the trial, "Gene Transfer for Severe Combined Immunodeficiency, X-linked (SCID-X1) Using a Self-inactivating (SIN) Gammaretroviral Vector" (NCT01129544), visit

For information on enrollment, contact Adam C. Simmons, MPH at Children's Hospital Boston (

For more on Severe Combined Immunodeficiency:


Rob Graham


Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including nine members of the National Academy of Sciences, 12 members of the Institute of Medicine and 13 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 397-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital and its research visit:

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