Gene Therapy for Immunodeficiency Due to Adenosine Deaminase Deficiency

Abstract

Gene therapy, combined with reduced-intensity conditioning, is a safe and effective treatment for SCID in patients with ADA deficiency. (ClinicalTrials.gov numbers, NCT00598481 and NCT00599781.)

In vivo T-cell dynamics during immune reconstitution after hematopoietic stem cell gene therapy in adenosine deaminase severe combined immune deficiency

“…Nevertheless, we did not find statistically significant differences within this cohort by comparing the absolute number of lymphocytes or T-cell subsets counts with respect to conditioning or diagnosis (data not shown; Fig E2). After GT, immune reconstitution occurs at a slower pace compared with that of the control BMT group 4,28 (see also Fig E2). This is in part expected because GT patients received an infusion of purified CD34 1 cells, whereas in our control group the HLA-identical graft was T-cell-replete.…”

“…14 Because we can exclude that mature T cells have been cotransplanted with the ex vivo cultured CD34 1 cells, the most likely explanation for the presence of phenotypically memory T cells is the survival of pre-existing, nontransduced circulating T cells, which were generated on enzyme replacement therapy. 4 Indeed, at early followup, a substantial proportion of the circulating naive and memory T cells was nontransduced (Fig E3). Gene-corrected cells became the majority over time because of the selective advantage for ADA 1 T cells, possibly occurring during peripheral expansion and/or antigen-specific stimulation.…”

“…NCT00598481 and NCT00599781). Seven patients with ADA-SCID have been described previously 4 ; the other 5 displayed typical early onset and were enrolled after failure or unavailability of long-term polyethylene glycol-ADA and were treated between 0.5 and 6.2 years of age (A. Aiuti, unpublished data). Patients received a single infusion of autologous CD34 1 cells transduced with GIADAl vector after busulfan infusion (4 mg/kg intravenously).…”

“…Long-term immune reconstitution has been achieved in gene therapy (GT) trials for severe combined immunodeficiency (SCID) caused by IL-2 receptor g [1][2][3] or adenosine deaminase (ADA) deficiency. [4][5][6] In patients with ADA-SCID, transplant of retrovirally transduced CD34 1 cells after low-intensity conditioning has resulted in longterm engraftment of multilineage HSCs 7 with correction of metabolic and immunologic defects. 4,8 After BMT or in lymphopenic conditions (ie, resulting from genetic or acquired immunodeficiencies or infections), the T-cell compartment can be sustained by (1) homeostatic proliferation of pre-existing T-cell clones, [9][10][11] (2) de novo thymopoiesis, or (3) extrathymic differentiation.…”

“…[4][5][6] In patients with ADA-SCID, transplant of retrovirally transduced CD34 1 cells after low-intensity conditioning has resulted in longterm engraftment of multilineage HSCs 7 with correction of metabolic and immunologic defects. 4,8 After BMT or in lymphopenic conditions (ie, resulting from genetic or acquired immunodeficiencies or infections), the T-cell compartment can be sustained by (1) homeostatic proliferation of pre-existing T-cell clones, [9][10][11] (2) de novo thymopoiesis, or (3) extrathymic differentiation. 12 After BMT, the reconstitution of the peripheral T cells is mainly driven by memory cells, particularly at early follow-up, in both pediatric and adult recipients.…”