Researchers have safely used gene therapy to treat eight baby boys born with an immune disorder known as “bubble boy” disease, named after a patient who grew up in the 1970s in a plastic enclosure to avoid germs. In the study, published 17 April in The New England Journal of Medicine, researchers used a harmless virus to insert a missing gene called IL2RG into bone marrow cells taken from infants with X-linked severe combined immunodeficiency disorder (X-SCID). The first X-SCID gene therapy trial 2 decades ago at first appeared successful, but some patients later developed leukemia because the new gene activated a cancer gene. The Scientist reports that the new study used a safer virus as well as chemotherapy to make room for the repaired cells, a step that more effectively restored the infants’ immune systems.
BACKGROUND
Allogeneic hematopoietic stem-cell transplantation for X-linked severe combined immunodeficiency (SCID-X1) often fails to reconstitute immunity associated with T cells, B cells, and natural killer (NK) cells when matched sibling donors are unavailable unless high-dose chemotherapy is given. In previous studies, autologous gene therapy with γ-retroviral vectors failed to reconstitute B-cell and NK-cell immunity and was complicated by vector-related leukemia.
METHODS
We performed a dual-center, phase 1–2 safety and efficacy study of a lentiviral vector to transfer IL2RGcomplementary DNA to bone marrow stem cells after low-exposure, targeted busulfan conditioning in eight infants with newly diagnosed SCID-X1.
RESULTS
Eight infants with SCID-X1 were followed for a median of 16.4 months. Bone marrow harvest, busulfan conditioning, and cell infusion had no unexpected side effects. In seven infants, the numbers of CD3+, CD4+, and naive CD4+ T cells and NK cells normalized by 3 to 4 months after infusion and were accompanied by vector marking in T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors. The eighth infant had an insufficient T-cell count initially, but T cells developed in this infant after a boost of gene-corrected cells without busulfan conditioning. Previous infections cleared in all infants, and all continued to grow normally. IgM levels normalized in seven of the eight infants, of whom four discontinued intravenous immune globulin supplementation; three of these four infants had a response to vaccines. Vector insertion-site analysis was performed in seven infants and showed polyclonal patterns without clonal dominance in all seven.
CONCLUSIONS
Lentiviral vector gene therapy combined with low-exposure, targeted busulfan conditioning in infants with newly diagnosed SCID-X1 had low-grade acute toxic effects and resulted in multilineage engraftment of transduced cells, reconstitution of functional T cells and B cells, and normalization of NK-cell counts during a median follow-up of 16 months. (Funded by the American Lebanese Syrian Associated Charities and others; LVXSCID-ND ClinicalTrials.gov number, NCT01512888.)