Research ArticleGene Therapy

Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency

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Science Translational Medicine  20 Apr 2016:
Vol. 8, Issue 335, pp. 335ra57
DOI: 10.1126/scitranslmed.aad8856

SCID gene therapy comes of age

Diseases caused by mutations in single genes are prime candidates for gene therapy. X-linked severe combined immunodeficiency (SCID-X1) patients have mutations in IL2RG, which encodes the common γ chain of several interleukin receptors, resulting in lack of adaptive immune cells. Gene therapy has shown promise in SCID infants but failed in older SCID-X1 children. Now, De Ravin et al. report that lentiviral gene therapy with nonmyeloablative conditioning corrected multiple immune cell types in five older SCID-X1 patients whose symptoms persisted despite undergoing hematopoietic stem cell transplant(s) as infants. Humoral immunity restoration with normal immunoglobulin production and responses to immunization is confirmed in the first two patients with longer follow-up.


X-linked severe combined immunodeficiency (SCID-X1) is a profound deficiency of T, B, and natural killer (NK) cell immunity caused by mutations in IL2RG encoding the common chain (γc) of several interleukin receptors. Gamma-retroviral (γRV) gene therapy of SCID-X1 infants without conditioning restores T cell immunity without B or NK cell correction, but similar treatment fails in older SCID-X1 children. We used a lentiviral gene therapy approach to treat five SCID-X1 patients with persistent immune dysfunction despite haploidentical hematopoietic stem cell (HSC) transplant in infancy. Follow-up data from two older patients demonstrate that lentiviral vector γc transduced autologous HSC gene therapy after nonmyeloablative busulfan conditioning achieves selective expansion of gene-marked T, NK, and B cells, which is associated with sustained restoration of humoral responses to immunization and clinical improvement at 2 to 3 years after treatment. Similar gene marking levels have been achieved in three younger patients, albeit with only 6 to 9 months of follow-up. Lentiviral gene therapy with reduced-intensity conditioning appears safe and can restore humoral immune function to posthaploidentical transplant older patients with SCID-X1.

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