Gene Therapy for Inborn Errors of Immunity.

In the early 1990s, gene therapy (GT) entered the clinical arena as an alternative to hematopoietic stem cell transplantation for forms of inborn errors of immunity (IEIs) that are not medically manageable because of their severity. In principle, the use of gene-corrected autologous hematopoietic stem cells presents several advantages over hematopoietic stem cell transplantation, including making donor searches unnecessary and avoiding the risks for graft-versus-host disease. In the past 30 years or more of clinical experience, the field has witnessed multiple examples of successful applications of GT to a number of IEIs, as well as some serious drawbacks, which have highlighted the potential genotoxicity of integrating viral vectors and stimulated important progress in the development of safer gene transfer tools. The advent of gene editing technologies promises to expand the spectrum of IEIs amenable to GT to conditions caused by mutated genes that require the precise regulation of expression or by dominant-negative variants. Here, we review the main concepts of GT as it applies to IEIs and the clinical results obtained to date. We also describe the challenges faced by this branch of medicine, which operates in the unprofitable sector of human rare diseases.