1. ¹Molecular Immunology Unit, Institute of Child Health, University College London, 30, Guilford Street, London WC1N 1EH, UK
2. ²Department of Clinical Immunology, Great Ormond Street Hospital NHS Trust, Great Ormond Street, London WC1N 3JH, UK
3. ³Bone Marrow Transplantation, Great Ormond Street Hospital NHS Trust, Great Ormond Street, London WC1N 3JH, UK
4. ⁴Purine Research Laboratory, Guys and St Thomas' Hospital, London Bridge Road, London SE1 9RT, UK

Correspondence: H. Bobby Gaspar, Molecular Immunology Unit, Institute of Child Health, University College London, 30, Guilford Street, London WC1N 1EH, UK Fax: +44 207 905 2810. E-mail: h.gaspar@ich.ucl.ac.uk.

Received 8 June 2006; Revised 27 June 2006; Accepted 27 June 2006.

Abstract

Gene therapy is a promising treatment option for monogenic diseases, but success has been seen in only a handful of studies thus far. We now document successful reconstitution of immune function in a child with the adenosine deaminase (ADA)-deficient form of severe combined immunodeficiency (SCID) following hematopoietic stem cell (HSC) gene therapy. An ADA-SCID child who showed a poor response to PEG-ADA enzyme replacement was enrolled into the clinical study. Following cessation of enzyme replacement therapy, autologous CD34⁺ HSCs were transduced with an ADA-expressing gammaretroviral vector. Gene-modified cells were reinfused following one dose of preconditioning chemotherapy. Two years after the procedure, immunological and biochemical correction has been maintained with progressive increase in lymphocyte numbers, reinitiation of thymopoiesis, and systemic detoxification of ADA metabolites. Sustained vector marking with detection of polyclonal vector integration sites in multiple cell lineages and detection of ADA activity in red blood cells suggests transduction of early hematopoietic progenitors. No serious side effects were seen either as a result of the conditioning procedure or due to retroviral insertion. Gene therapy is an effective treatment option for the treatment of ADA-SCID.