Efficacy of Gene Therapy for X-linked Severe Combined Immunodeficiency

Efficacy of Gene Therapy for X-linked Severe Combined Immunodeficiency

Salima Hacein-Bey-Abina, Pharm.D., Ph.D., Julia Hauer, M.D., Annick Lim, M.Sci., Capucine Picard, M.D., Ph.D., Gary P. Wang, M.D., Ph.D., Charles C. Berry, Ph.D., Chantal Martinache, M.Sci., Frédéric Rieux-Laucat, Ph.D., Sylvain Latour, Ph.D., Bernd H. Belohradsky, M.D., Lily Leiva, Ph.D., Ricardo Sorensen, M.D., Marianne Debré, M.D., Jean Laurent Casanova, M.D., Ph.D., Stephane Blanche, M.D., Anne Durandy, M.D., Ph.D., Frederic D. Bushman, Ph.D., Alain Fischer, M.D., Ph.D. and Marina Cavazzana-Calvo, M.D., Ph.D.

N Engl J Med 2010; 363:355-364July 22, 2010

Background

The outcomes of gene therapy to correct congenital immunodeficiencies are unknown. We reviewed long-term outcomes after gene therapy in nine patients with X-linked severe combined immunodeficiency (SCID-X1), which is characterized by the absence of the cytokine receptor common γ chain.

Methods

The nine patients, who lacked an HLA-identical donor, underwent ex vivo retrovirus-mediated transfer of γ chain to autologous CD34+ bone marrow cells between 1999 and 2002. We assessed clinical events and immune function on long-term follow-up.

Results

Eight patients were alive after a median follow-up period of 9 years (range, 8 to 11). Gene therapy was initially successful at correcting immune dysfunction in eight of the nine patients. However, acute leukemia developed in four patients, and one died. Transduced T cells were detected for up to 10.7 years after gene therapy. Seven patients, including the three survivors of leukemia, had sustained immune reconstitution; three patients required immunoglobulin-replacement therapy. Sustained thymopoiesis was established by the persistent presence of naive T cells, even after chemotherapy in three patients. The T-cell−receptor repertoire was diverse in all patients. Transduced B cells were not detected. Correction of the immunodeficiency improved the patients’ health.

Conclusions

After nearly 10 years of follow-up, gene therapy was shown to have corrected the immunodeficiency associated with SCID-X1. Gene therapy may be an option for patients who do not have an HLA-identical donor for hematopoietic stem-cell transplantation and for whom the risks are deemed acceptable. This treatment is associated with a risk of acute leukemia. (Funded by INSERM and others.)

linkback url: http://www.nejm.org/doi/pdf/10.1056/NEJMoa1000164

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