Gene therapy for immunodeficiency due to adenosine deaminase deficiency

N Engl J Med. 2009 Jan 29;360(5):447-58. doi: 10.1056/NEJMoa0805817.

Abstract

Background: We investigated the long-term outcome of gene therapy for severe combined immunodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency.

Methods: We infused autologous CD34+ bone marrow cells transduced with a retroviral vector containing the ADA gene into 10 children with SCID due to ADA deficiency who lacked an HLA-identical sibling donor, after nonmyeloablative conditioning with busulfan. Enzyme-replacement therapy was not given after infusion of the cells.

Results: All patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transduced hematopoietic stem cells have stably engrafted and differentiated into myeloid cells containing ADA (mean range at 1 year in bone marrow lineages, 3.5 to 8.9%) and lymphoid cells (mean range in peripheral blood, 52.4 to 88.0%). Eight patients do not require enzyme-replacement therapy, their blood cells continue to express ADA, and they have no signs of defective detoxification of purine metabolites. Nine patients had immune reconstitution with increases in T-cell counts (median count at 3 years, 1.07x10(9) per liter) and normalization of T-cell function. In the five patients in whom intravenous immune globulin replacement was discontinued, antigen-specific antibody responses were elicited after exposure to vaccines or viral antigens. Effective protection against infections and improvement in physical development made a normal lifestyle possible. Serious adverse events included prolonged neutropenia (in two patients), hypertension (in one), central-venous-catheter-related infections (in two), Epstein-Barr virus reactivation (in one), and autoimmune hepatitis (in one).

Conclusions: Gene therapy, combined with reduced-intensity conditioning, is a safe and effective treatment for SCID in patients with ADA deficiency. (ClinicalTrials.gov numbers, NCT00598481 and NCT00599781.)

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Deaminase / deficiency
  • Adenosine Deaminase / genetics*
  • Antigens, CD34 / genetics*
  • Bone Marrow Cells / immunology
  • Child, Preschool
  • Combined Modality Therapy
  • Follow-Up Studies
  • Genetic Therapy*
  • Genetic Vectors
  • Hematopoietic Stem Cell Transplantation*
  • Humans
  • Infant
  • Lymphocyte Count
  • Retroviridae
  • Severe Combined Immunodeficiency / immunology
  • Severe Combined Immunodeficiency / therapy*
  • Transduction, Genetic
  • Transplantation Conditioning

Substances

  • Antigens, CD34
  • Adenosine Deaminase

Associated data

  • ClinicalTrials.gov/NCT00598481
  • ClinicalTrials.gov/NCT00599781