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

• Published in: Blood Vol. 120; no. 18; pp. 3635 - 3646
• Main Authors: Candotti, Fabio, Shaw, Kit L., Muul, Linda, Carbonaro, Denise, Sokolic, Robert, Choi, Christopher, Schurman, Shepherd H., Garabedian, Elizabeth, Kesserwan, Chimene, Jagadeesh, G. Jayashree, Fu, Pei-Yu, Gschweng, Eric, Cooper, Aaron, Tisdale, John F., Weinberg, Kenneth I., Crooks, Gay M., Kapoor, Neena, Shah, Ami, Abdel-Azim, Hisham, Yu, Xiao-Jin, Smogorzewska, Monika, Wayne, Alan S., Rosenblatt, Howard M., Davis, Carla M., Hanson, Celine, Rishi, Radha G., Wang, Xiaoyan, Gjertson, David, Yang, Otto O., Balamurugan, Arumugam, Bauer, Gerhard, Ireland, Joanna A., Engel, Barbara C., Podsakoff, Gregory M., Hershfield, Michael S., Blaese, R. Michael, Parkman, Robertson, Kohn, Donald B.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.11.2012; Americain Society of Hematology; American Society of Hematology
• Subjects: Adenosine Deaminase - deficiency; Adolescent; Agammaglobulinemia - therapy; Antigens, CD34 - metabolism; Biological and medical sciences; Bone Marrow Transplantation - methods; Child; Child, Preschool; Clinical Trials and Observations; Female; Gene Therapy; Genetic Therapy - methods; Genetic Vectors; Hematologic and hematopoietic diseases; Hematopoietic Stem Cell Transplantation - methods; Humans; Infant; Male; Medical sciences; Plenary Paper; Retroviridae - genetics; Severe Combined Immunodeficiency - therapy; Transduction, Genetic; Transplantation Conditioning; Young Adult; Virus; Immunopathology; Treatment; Hematology; Severe combined immunodeficiency; Enzyme; Retroviridae; Hydrolases; Adenosine deaminase; Gene therapy; Vector; Comparative study
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2012-02-400937

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.