Advances in SCID (“bubble boy” disease): A Q&A with a child hematologist/oncologist

David Williams, Luigi Notarangelo and Sun-Yung PaiSung-Yun Pai, MD, a pediatric hematologist/oncologist at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, was lead author on two recent articles on severe combined immune deficiency (SCID) in The New England Journal of Medicine. The first reviewed outcomes after bone marrow transplantation; the second reported the first results of a new international gene therapy trial for X-linked SCID. Here, she discusses what’s known to date about these therapies.

Q: What is SCID?

A: SCID is a group of disorders that compromise the blood’s T cells, a key component of the immune system that helps the body fight common viral infections, other opportunistic infections and fungal infections. T-cells are also important for the development of antibody responses to bacteria and other microorganisms. A baby born with SCID appears healthy at birth, but once the maternal antibodies that the baby is born with start to wane, the infant is at risk for life-threatening infections. Unless diagnosed and treated—with a stem cell transplant from a healthy donor or a more experimental therapy like gene therapy—babies with SCID typically die before their first birthday.

Q: What role does stem cell transplant play in SCID, and how effective is it?

A: Stem cell transplantation involves infusing healthy donor blood stem cells, which can be derived from a variety of sources; it has been described for SCID since 1968. The ideal donor is a healthy sibling with a matched tissue type. However, only 25 percent of siblings will be a matched donor, and fewer still will not themselves have SCID. For most patients, the donor is a parent, an unrelated suitably matched adult or an umbilical cord donor.

David Vetter, who died at age 12 in 1984, was a famous SCID patient who lived his life in a plastic bubble to avoid infections.
David Vetter was a famous SCID patient who lived in a plastic bubble to avoid infections, before any SCID treatments were available. He died in 1984 at the age of 12. (Image via pixshark.com)

In our recent study, we examined outcomes for 240 patients transplanted in North America between 2000 and 2010. Virtually all patients with a matched sibling donor survived, but only half of babies who were actively infected at the time of transplant survived. Babies who had never suffered an infection or whose infection had resolved prior to transplant had excellent survival, regardless of age or donor source. The longer you wait for transplant, the more likely it is that a baby with SCID will develop an infection, making it important to transplant babies as soon after birth as possible. Newborn screening, now in effect in 27 states and the District of Columbia, is critical for this.

Actively infected babies who got chemotherapy or immunosuppressive conditioning before transplant (to prevent rejection) had dismal survival compared to those who received no conditioning. While overall we found better immune system recovery in surviving babies who received chemotherapy conditioning, this benefit must be weighed against the long- and short-term toxicities of chemotherapy.

Q: What is gene therapy, and how can it help SCID?

A: Gene therapy is an experimental treatment currently available for X-linked SCID and adenosine deaminase deficiency SCID (ADA SCID). Clinicians harvest the patient’s own blood stem cells, introduce a corrected copy of the gene into a specially designed virus called a vector, and give the corrected cells to the patient through a transplant. Because the patient’s own cells are used, gene therapy eliminates the risk of graft-versus-host disease.

Q: What results have you seen?

A: The new trial for X-linked SCID was designed to avoid the treatment-related leukemia that developed in one-quarter of patients in earlier European trials. We found that a redesigned vector is equally effective in curing the SCID, and we have preliminary evidence that it is safer. Although our patients have not yet cleared the two-to-five year window in which the leukemia developed in the earlier trials, a molecular analysis shows that the new vector did not lead to the proliferation of cells seen in those trials, driven by over-activity of cancer-causing genes.

Q: Who should receive conventional transplant, and who should get gene therapy?

A: If you have a matched sibling donor you should go with transplant. These transplants are almost always performed without chemotherapy, so even babies with an active infection do well. They are at substantially lower risk of graft-versus-host disease and rarely get its severe form.

Candidates for gene therapy include patients who lack a matched sibling donor, as well as those with an active infection. While most patients who undergo transplant do not develop severe graft-versus-host disease, the consequences can be debilitating for those that do. Gene therapy trials for ADA SCID have yielded such positive results and are so far along that it is becoming standard of care for some patients and is beginning to be covered by insurance.

Q: Looking ahead, what do you see?

A: Given the toxicity of chemotherapy conditioning, we would like to determine the minimal dose needed to give patients the best chance of having normal immune systems. In gene therapy, we are working on the next generation vector, which we hope will be even less prone to causing leukemia, and plan to introduce a moderate dose of chemotherapy conditioning to promote better immune system recovery. Both avenues of treatment are clearly advancing. It’s too soon to say whether one will take over for the other. Ultimately I hope to see that all babies with SCID can be cured.