Blood Journal
Leading the way in experimental and clinical research in hematology

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

  1. Fabio Candotti1,
  2. Kit L. Shaw2,
  3. Linda Muul1,
  4. Denise Carbonaro2,
  5. Robert Sokolic1,
  6. Christopher Choi2,
  7. Shepherd H. Schurman1,
  8. Elizabeth Garabedian1,
  9. Chimene Kesserwan1,
  10. G. Jayashree Jagadeesh1,
  11. Pei-Yu Fu2,
  12. Eric Gschweng2,
  13. Aaron Cooper3,
  14. John F. Tisdale4,
  15. Kenneth I. Weinberg5,
  16. Gay M. Crooks6,
  17. Neena Kapoor7,
  18. Ami Shah7,
  19. Hisham Abdel-Azim7,
  20. Xiao-Jin Yu7,
  21. Monika Smogorzewska7,
  22. Alan S. Wayne8,
  23. Howard M. Rosenblatt9,
  24. Carla M. Davis10,
  25. Celine Hanson10,
  26. Radha G. Rishi11,
  27. Xiaoyan Wang12,
  28. David Gjertson12,
  29. Otto O. Yang13,
  30. Arumugam Balamurugan13,
  31. Gerhard Bauer14,
  32. Joanna A. Ireland7,
  33. Barbara C. Engel15,
  34. Gregory M. Podsakoff16,
  35. Michael S. Hershfield17,
  36. R. Michael Blaese18,
  37. Robertson Parkman7, and
  38. Donald B. Kohn2,*
  1. 1 Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States;
  2. 2 Departments of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles David Geffen School of Medicine, Los Angeles, CA, United States;
  3. 3 Molecular Biology Interdepartmental PhD Program, University of California, Los Angeles David Geffen School of Medicine, Los Angeles, CA, United States;
  4. 4 Molecular and Clinical Hematology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States;
  5. 5 Department of Pediatrics, Stanford School of Medicine, Stanford, CA, United States;
  6. 6 Department of Pathology & Laboratory Medicine, University of California, Los Angeles David Geffen School of Medicine, Los Angeles, CA, United States;
  7. 7 Division of Research Immunology/Bone Marrow Transplant, Department of Pediatrics, Childrens Hospital, Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, United States;
  8. 8 Hematologic Diseases Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States;
  9. 9 Hematology/Oncology, Dell Children's Medical Center of Central Texas, Austin, TX, United States;
  10. 10 Department of Pediatrics, Section of Allergy and Immunology, Texas Children's Hospital, Houston, TX, United States;
  11. 11 Arizona Allergy Associates, Scottsdale, AZ, United States;
  12. 12 Department of Biostatistics, School of Public Health, University of California, Los Angeles, Los Angeles, CA, United States;
  13. 13 Division of Infectious Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States;
  14. 14 Division of Hematology Oncology, Department of Internal Medicine, University of California Davis School of Medicine, Sacramento, CA, United States;
  15. 15 The Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, United States;
  16. 16 Division of Hematology and Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States;
  17. 17 Departments of Medicine and Biochemistry, Duke University School of Medicine, Durham, NC, United States;
  18. 18 Immune Deficiency Foundation, Towson, MD, United States
  1. * Corresponding author; email: dkohn{at}mednet.ucla.edu

Abstract

We conducted a gene therapy trial in 10 patients with adenosine deaminase-deficient severe combined immunodeficiency (ADA-deficient SCID) using two slightly different retroviral vectors for the transduction of patients' bone marrow CD34+ cells. Four subjects were treated without pre-transplant cytoreduction and remained on ADA enzyme replacement therapy (ERT) throughout the procedure. Only transient (months), low level (<0.01%) gene marking was seen in peripheral blood mononuclear cells (PBMC) of two older subjects (15 and 20 years old), whereas some gene marking of PBMC has persisted for the past nine years in two 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 post-procedure), 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 due to poor gene marking and immune recovery and one had a subsequent allogeneic hematopoietic stem cell transplant. These studies directly demonstrate the importance of providing non-myeloablative pre-transplant conditioning to achieve therapeutic benefits with gene therapy for ADA-deficient SCID.

  • Submitted February 2, 2012.
  • Accepted July 31, 2012.