Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans.
We conducted a gene therapy trial in 10 patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency using 2 slightly different retroviral vectors for the transduction of patients' bone marrow CD34(+) cells. Four subjects were treated without pretransplantation cytoreduction and remained on ADA enzyme-replacement therapy (ERT) throughout the procedure. Only transient (months), low-level (< 0.01%) gene marking was observed in PBMCs of 2 older subjects (15 and 20 years of age), whereas some gene marking of PBMC has persisted for the past 9 years in 2 younger subjects (4 and 6 years). Six additional subjects were treated using the same gene transfer protocol, but after withdrawal of ERT and administration of low-dose busulfan (65-90 mg/m(2)). Three of these remain well, off ERT (5, 4, and 3 years postprocedure), with gene marking in PBMC of 1%-10%, and ADA enzyme expression in PBMC near or in the normal range. Two subjects were restarted on ERT because of poor gene marking and immune recovery, and one had a subsequent allogeneic hematopoietic stem cell transplantation. These studies directly demonstrate the importance of providing nonmyeloablative pretransplantation conditioning to achieve therapeutic benefits with gene therapy for ADA-deficient severe combined immunodeficiency.
Candotti, F; Shaw, KL; Muul, L; Carbonaro, D; Sokolic, R; Choi, C; Schurman, SH; Garabedian, E; Kesserwan, C; Jagadeesh, GJ; Fu, P-Y; Gschweng, E; Cooper, A; Tisdale, JF; Weinberg, KI; Crooks, GM; Kapoor, N; Shah, A; Abdel-Azim, H; Yu, X-J; Smogorzewska, M; Wayne, AS; Rosenblatt, HM; Davis, CM; Hanson, C; Rishi, RG; Wang, X; Gjertson, D; Yang, OO; Balamurugan, A; Bauer, G; Ireland, JA; Engel, BC; Podsakoff, GM; Hershfield, MS; Blaese, RM; Parkman, R; Kohn, DB
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