Gene Therapy in Infants with Severe Combined Immunodeficiency Makoto Otsu and Fabio Candotti Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 1. Severe Combined Immunodeficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 2. Management of Patients with Severe Combined Immunodeficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 2.1 General Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 2.2 Allogeneic Bone Marrow Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 2.3 Enzyme Replacement Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 3. Gene Therapy as an Alternative Therapeutic Option for Severe Combined Immunodeficiencies . . . . . . . . . . . . . . . . 231 4. Advances in Gene Transfer Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 4.1 Retroviral Vectors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 4.2 Lentiviral Vectors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 4.3 Ex Vivo Manipulation of Target Cells and Transduction Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 5. Gene Therapy for Severe Combined Immunodeficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 5.1 Adenosine Deaminase Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 5.2 X-Linked Severe Combined Immunodeficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 5.3 Other Severe Combined Immunodeficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 6. Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236 Abstract Severe combined immunodeficiencies (SCID) are rare disorders that represent paediatric medical emergen- cies, as the outcome for affected patients can easily be fatal unless proper treatment is performed. The only curative treatment for SCID is reconstitution of the patient’s immunity. For more than 30 years, allogeneic bone marrow transplantation (BMT) has been extremely successful for SCID. However, BMT often results in only incomplete restoration of B cell function in treated patients, especially when haploidentical donors are used. In addition, BMT can be associated with severe complications such as graft-versus-host disease (GVHD). Alter- native forms of therapy for SCID are therefore desirable. Genetic correction of peripheral T lymphocytes and/or haematopoietic stem cells (HSCs) by retrovirally mediated gene transfer has been attempted for patients with SCID due to adenosine deaminase deficiency, the first genetic disease targeted in clinical gene therapy trials with very limited success, overall. After these pioneer trials, recent progress has led to significant improvement of gene transfer techniques and better understanding of HSC biology which has culminated in the recent success of a gene therapy trial for patients affected with X-linked SCID (X-SCID). In this trial, patients with X-SCID received autologous bone marrow stem/progenitor cells which had been retrovirally transduced with a thera- peutic gene. Based on the current follow-up, the overall efficacy of this gene therapy procedure is to be consid- ered similar to or even better than that achievable by allogeneic BMT, because patients were not exposed to the risks of GVHD. Although these exciting results have clearly demonstrated that gene therapy is a feasible therapeutic option for X-SCID, they have also raised important questions regarding the long-term outcome of this experimental procedure and the possibility of translating this success into applications for other forms of SCID. GENE THERAPY Biodrugs 2002; 16 (4): 229-239 1173-8804/02/0004-0229/$25.00/0 © Adis International Limited. All rights reserved.