Outcomes in Two Japanese Adenosine Deaminase-Deficiency Patients Treated by Stem Cell Gene Therapy with No Cytoreductive Conditioning

Abstract

ObjectiveWe here describe treatment outcomes in two adenosine deaminase (ADA)-deficiency patients (pt) who received stem cell gene therapy (SCGT) with no cytoreductive conditioning. As this protocol has features distinct from those of other clinical trials, its results provide insights into SCGT for ADA deficiency. Patients and MethodsPt 1 was treated at age 4.7 years, whereas pt 2, who had previously received T-cell gene therapy, was treated at age 13 years. Bone marrow CD34 + cells were harvested after enzyme replacement therapy (ERT) was withdrawn; following transduction of ADA cDNA by the -retroviral vector GCsapM-ADA, they were administered intravenously. No cytoreductive conditioning, at present considered critical for therapeutic benefit, was given before cell infusion. Hematological/immunological reconstitution kinetics, levels of systemic detoxification, gene-marking levels, and proviral insertion sites in hematopoietic cells were assessed. ResultsTreatment was well tolerated, and no serious adverse events were observed.Engraftment of gene-modified repopulating cells was evidenced by the appearance and maintenance of peripheral lymphocytes expressing functional ADA. Systemic detoxification was moderately achieved, allowing temporary discontinuation of ERT for 6 and 10 years in pt 1 and pt 2, respectively. Recovery of immunity remained partial, with lymphocyte counts in patients 1 and 2, peaked at 408/mm 3 and 1248/mm 3 , approximately 2 and 5 years after SCGT. Vector integration site analyses confirmed that hematopoiesis was reconstituted with a limited number of clones, some of which were shown to have myelo-lymphoid potential. ConclusionsOutcomes in SCGT for ADA-SCID are described in the context of a unique protocol, which used neither ERT nor cytoreductive conditioning. Although proven safe, immune reconstitution was partial and temporary. Our results reiterate the importance of cytoreductive conditioning to ensure greater benefits from SCGT.Otsu et al.

Reactive oxygen species in hematopoietic stem cells affect culture outcomes under inflammatory conditions

“…A favorable influence of TGF-β on HSC retention is consistent with our previous reports [13,15]. Positive effects of IL-6 on HSC culture are well known, as exemplified by its use in a cytokine cocktail in clinical trials [16][17] where expansion of human CD34+ cells was the goal. That IL-1β promoted retention of primitive cells is an unexpected observation in light of its reportedly negative effects on HSCs' reconstituting ability [18].…”

Single Cell-Based Vector Tracing in Patients with ADA-SCID Treated with Stem Cell Gene Therapy

“…In 2015, we reported two patients with ADA-SCID who were treated with retrovirus-mediated gene therapy 18 . Although PEG-ADA replacement was withdrawn in our trial, the patients never received preconditioning chemotherapy before the transplantation of gene-modified HSCs; therefore, partial and temporal reconstitution of the immune system was observed in both patients.…”

Current status of ex vivo gene therapy for hematological disorders: a review of clinical trials in Japan around the world

“…Vector integration-site analyses confirmed that hematopoiesis was reconstituted by a limited number of clones, some of which had myelo-lymphoid potential. These results emphasize that cytoreductive conditioning is important for achieving optimal benefits from SCGT [30] (Table 3).…”