Lentiviral Gene Therapy Combined with Low-Dose Busulfan in Infants with SCID-X1

Abstract

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 IL2RG complementary 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 in-fants 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, .)

Intrathymic adeno-associated virus gene transfer rapidly restores thymic function and long-term persistence of gene-corrected T cells

“…Adverse events caused by insertional mutagenesis of gammaretroviral vectors [13][14][15][16] have resulted in the development of lentivirus-based clinical trials for patients with SCID. Notably, mutagenesis has not been reported in the latter, 5,17,18 but it is still important to continue to explore and develop new therapeutic strategies.…”

Intrathymic delivery a new route for adenoviral-associated vector gene therapy

“…In the last decade, gene therapy trials based on the infusion of autologous gene-corrected HSCs performed in X-linked SCID and adenosine deaminase (ADA)-SCID as well as in Wiskott-Aldrich syndrome demonstrated the safety and efficacy of this strategy. [2][3][4] T-cell differentiation occurs in the thymus; thus, it has been hypothesized that intrathymic injection of HSCs or progenitors would improve T-cell output and reconstitution in patients with SCID and combined immunodeficiency (Fig 1, A). In preclinical models of SCID and ZAP-70 deficiency, it was indeed shown that intrathymic injection of bone marrow progenitors is a safe procedure and represents an effective strategy to generate protective T-cell immunity.…”

Gene therapy for severe combined immunodeficiencies and beyond

“…3). In a recent publication on a multicenter study of SCID X1 (Mamcarz et al, 2019), the combination of mild chemotherapy with use of a SIN IL2RG LV vector resulted in the reconstitution of T cell, NK cell, and (to a lesser extent) B cell function in seven of the eight treated patients, with a follow-up period of ≤21 mo. These preliminary results are encouraging in terms of both safety and efficacy.…”