Gene therapy for adenosine deaminase–deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans

F Candotti, KL Shaw, L Muul… - Blood, The Journal …, 2012 - ashpublications.org
F Candotti, KL Shaw, L Muul, D Carbonaro, R Sokolic, C Choi, SH Schurman, E Garabedian…
Blood, The Journal of the American Society of Hematology, 2012ashpublications.org
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 …
Abstract
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/m2). 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.
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