Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: clinical comparison of retroviral vectors and treatment plans
Fabio Candotti, Kit L Shaw, Linda Muul, Denise Carbonaro, Robert Sokolic, Christopher Choi, Shepherd H Schurman, Elizabeth Garabedian, Chimene Kesserwan, G Jayashree Jagadeesh, Pei-Yu Fu, Eric Gschweng, Aaron Cooper, John F Tisdale, Kenneth I Weinberg, Gay M Crooks, Neena Kapoor, Ami Shah, Hisham Abdel-Azim, Xiao-Jin Yu, Monika Smogorzewska, Alan S Wayne, Howard M Rosenblatt, Carla M Davis, Celine Hanson, Radha G Rishi, Xiaoyan Wang, David Gjertson, Otto O Yang, Arumugam Balamurugan, Gerhard Bauer, Joanna A Ireland, Barbara C Engel, Gregory M Podsakoff, Michael S Hershfield, R Michael Blaese, Robertson Parkman, Donald B Kohn, Fabio Candotti, Kit L Shaw, Linda Muul, Denise Carbonaro, Robert Sokolic, Christopher Choi, Shepherd H Schurman, Elizabeth Garabedian, Chimene Kesserwan, G Jayashree Jagadeesh, Pei-Yu Fu, Eric Gschweng, Aaron Cooper, John F Tisdale, Kenneth I Weinberg, Gay M Crooks, Neena Kapoor, Ami Shah, Hisham Abdel-Azim, Xiao-Jin Yu, Monika Smogorzewska, Alan S Wayne, Howard M Rosenblatt, Carla M Davis, Celine Hanson, Radha G Rishi, Xiaoyan Wang, David Gjertson, Otto O Yang, Arumugam Balamurugan, Gerhard Bauer, Joanna A Ireland, Barbara C Engel, Gregory M Podsakoff, Michael S Hershfield, R Michael Blaese, Robertson Parkman, Donald B Kohn
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/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.
Figures
Source: PubMed