Purpose of review: Haematopoietic stem cell transplantation (HSCT) is the mainstay of definitive treatment for children with a wide spectrum of primary immunodeficiencies (PIDs), but outcome is heavily dependent on the availability of a human leukocyte antigen-matched donor. Gene therapy using autologous gene-corrected haematopoietic stem cells is an alternative for patients who lack an appropriate donor and has been used to treat children and adults with specific forms of PID, such as severe combined immunodeficiency, for over 10 years. This review summarizes the encouraging long-term outcome data available from these clinical trials and considers the important adverse events that have arisen. Current strategies directed towards improving the efficacy and safety profile of gene therapy will be discussed.
Recent findings: Effective clinical trials have been conducted for other forms of PID including chronic granulomatous disease and Wiskott-Aldrich syndrome. Preclinical and clinical studies are now focussed on the development of improved viral vectors giving more regulated or tissue-specific transgene expression with reduced mutagenic potential.
Summary: Gene therapy offers a valuable alternative management option for selected immunodeficiency patients who lack a suitable donor for HSCT. Clinical trials have confirmed proof-of-principle in terms of stem cell transduction and subsequent immune reconstitution, but have also highlighted the potential for clonal disturbances related to semi-random vector insertion within the genome.