Gene therapy for severe combined immunodeficiencies

Abstract

Severe combined immune deficiencies (SCIDs) are a group of monogenic diseases resulting in profound disturbances of lymphocyte development and function. Affected individuals are prone to life-threatening infections and without treatment do not survive beyond the first year of life. Haematopoietic stem cell transplantation from a well-matched donor offers high rates of survival, but in the absence of a suitable matched donor, parental haploidentical transplants are associated with greater complications, lower success rates and in some instances poor long-term immune recovery. Alternative therapeutic options based on correction of the defective gene by retroviral gene delivery have been used to correct X-linked SCID (SCID-X1) and adenosine deaminase-deficient SCID (ADA-SCID). A number of clinical trials have established that ex vivo gene transfer into haematopoietic progenitor cells allows effective recovery of immune defects and that gene therapy can offer a successful alternative to transplantation. The development of leukaemia as a result of insertional mutagenesis in one trial of gene therapy for SCID-X1 has raised concerns regarding the toxicity of retroviral vector-based gene delivery. These side effects are now being studied in detail and measures to prevent such events through alternative vectors delivery systems are in development at present.