Research ArticleImmunodeficiency

Hematopoietic Stem Cell Gene Therapy for Adenosine Deaminase–Deficient Severe Combined Immunodeficiency Leads to Long-Term Immunological Recovery and Metabolic Correction

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Science Translational Medicine  24 Aug 2011:
Vol. 3, Issue 97, pp. 97ra80
DOI: 10.1126/scitranslmed.3002716

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Out of the Bubble

As part of a normal day, most people will flush a toilet, open a door, or drink from a water fountain without even thinking about it—or about the lurking pathogens poised to infect us. We are afforded this luxury because of our immune system, which responds rapidly and specifically to just about anything thrown at it. Yet, for people with severe combined immunodeficiency (SCID), who carry a mutation that thwarts adaptive immunity, everyday activities can be deadly. Like the famous “bubble boy,” some people with SCID choose to live in a germ-free environment. Yet, matched hematopoietic stem cell (HSC) transplantation, which can replace the patient’s ailing immune system with functional cells from a related donor, can offer these patients a normal life. Sometimes, however, donor relatives aren’t available. Now, two new studies provide clinical support for treatment options that may allow SCID patients without matched donors to live relatively normal lives as well.

One such treatment option is gene therapy. Removing HSCs from SCID patients, repairing the underlying genetic defect in these cells, and returning the repaired cells to the original host can replace the faulty immune system in SCID patients without the graft rejection or graft-versus-host disease that follows transplantation of cells from unrelated donors. Gaspar et al. do just that for two types of SCID: X-linked SCID (SCID-X1) and adenosine deaminase–deficient SCID (ADA-SCID). The authors repaired the underlying genetic defect in 10 of 10 patients with SCID-X1 and in 4 of 6 patients with ADA-SCID, resulting in the development of a functional polyclonal T cell repertoire that persisted for at least 9 years after therapy. The procedure produced minimal side effects and permitted all patients to attend typical schools. One patient in the SCID-X1 cohort developed a blood cancer, acute lymphoblastic leukemia (ALL), a complication observed in previous SCID-X1 gene therapy studies, but this patient is currently in remission. No cases of ALL developed in the ADA-SCID cohort.

The promising results of these and similar studies, albeit with an increased risk of ALL in SCID-X1 patients, support the development of new safer and more efficient vectors for this and other kinds of gene therapy. Long-term follow-up of patient participants in early gene-therapy trials such as the ones described here is critical for scientists to decipher the parameters of success and failure for gene therapy in general—and for SCID-specific treatments to bubble over into the clinic.

Footnotes

  • Citation: H. B. Gaspar, S. Cooray, K. C. Gilmour, K. L. Parsley, F. Zhang, S. Adams, E. Bjorkegren, J. Bayford, L. Brown, E. G. Davies, P. Veys, L. Fairbanks, V. Bordon, T. Petropolou, C. Kinnon, A. J. Thrasher, Hematopoietic Stem Cell Gene Therapy for Adenosine Deaminase–Deficient Severe Combined Immunodeficiency Leads to Long-Term Immunological Recovery and Metabolic Correction. Sci. Transl. Med. 3, 97ra80 (2011).