Gene Therapy Proves Promising for Children with “Bubble Boy” Disease

Treatment of X-linked severe combined immunodeficiency (SCID-X1), a rare immune disorder also known as “bubble boy disease,” often involves stem cell transplantation from a matched sibling or unrelated donor to replace the patient’s diseased stem cells with healthy donor cells. In the absence of a fully matched stem cell donor, children with SCID-X1 may receive a transplant from a partial, or “half-matched,” donor. Patients may also benefit from a completely different approach – gene therapy.

Children with SCID-X1 are born with a genetic defect that prevents them from developing a normal immune system, characterized by a complete block in the development of T cells. Because they are prone to life-threatening infections, infants with SCID-X1 must be kept in a sterile, protective bubble and require extensive treatment for survival beyond infancy.

Gene therapy involves extracting an infant’s own bone marrow, using a virus to replace faulty genetic material with a correct copy, and then giving “corrected” bone marrow back to the patient. While this approach has been effective in correcting the T-cell immunodeficiency associated with SCID-X1, there have been no comparisons of outcomes with gene therapy and half-matched stem cell transplantation.

In a retrospective study, investigators retrospectively analyzed and compared clinical outcomes and immune reconstitution in SCID-X1 patients who had undergone HLA-mismatched HSCT or gene therapy. Fabien Touzot, MD, PhD, and colleagues found that patients receiving gene therapy had fewer infections and hospitalizations than those receiving partially matched stem cells.

“Over the last decade, gene therapy has emerged as a viable alternative to a partial matched stem cell transplant for infants with SCID-X1,” said Dr. Touzot, from Necker Children’s Hospital in Paris, France. “To ensure that we are providing the best alternative therapy possible, we wanted to compare outcomes between infants treated with gene therapy and infants receiving partial matched transplants.”

Dr. Touzot and colleagues studied the medical records of 27 children diagnosed with SCID-X1 between March 1999 and December 2013; 13 patients received partial-matched transplant and 14 received gene therapy. Patients were followed for a median of 6 and 12 years, respectively.

The researchers compared T-cell development among patients, as well as key clinical outcomes, such as infections and hospitalization.

Compared with children in the half-matched transplant group, the 14 children who underwent gene therapy developed healthy immune cells faster. In fact, six months after treatment, 11 of the 14 gene-therapy patients (78%) had normal T-cell count values, while only four of the 15 transplant patients (26%) had normal T-cell values at that point (p=0.02 for CD3+; p=0.05 for CD4; p=0.002 for CD8).

Gene therapy patients also had higher levels of CD3, CD4, and CD8 cells at six and 12 months following treatment. The median level of circulating regulatory CD4+ lymphocytes was significantly higher in gene therapy patients than in transplant patients at last follow-up (62/μL and 8.5/μL, respectively; p=0.01).

In addition to providing better clinical outcomes, gene therapy avoids some of the complications associated with allogeneic transplantation, including the limited availability of matched donors and the risk of graft failure, and end-organ damage through mechanisms like graft-versus-host disease.
In this study, seven patients in the transplant group had immune complications that required immunosuppressive therapy and further delayed immune reconstitution. And, even when Dr. Touzot and investigators excluded patients with graft failure (9 patients), they still observed a tendency toward faster T-cell compartment development in patients treated with gene therapy.

The more rapid reconstitution of the immune system in patients who received gene therapy was also associated with faster resolution of some opportunistic infections (11 months in the gene therapy group vs. 25.5 months in half-matched transplant group; p=0.029). There were three infection-related hospitalizations in the gene therapy group and 15 in the half-matched transplant group. The number of days of infection-related hospitalization was greater in the half-matched transplant group versus the gene therapy group (0.04 days vs. 0.03 days per patient per year; p=0.001).

“Our analysis suggests that gene therapy can put these incredibly sick children on the road to defending themselves against infection faster than a half-matched transplant,” Dr. Touzot said. “These results suggest that, for patients without a fully matched stem cell donor, gene therapy is the next-best approach.”


Touzot F, Moshous D, Creidy R, et al. Faster T-cell development following gene therapy compared to haplo-identical hematopoietic stem cell transplantation in the treatment of SCID-X1. Blood. 2015 April 13. [Epub ahead of print]