Gene therapy for inborn errors of immunity: current clinical progress.

Abstract

Hematopoietic stem cell transplant has been the single curative treatment for inborn errors of immunity (IEI) and is recommended for the most severe IEI conditions, such as severe combined immunodeficiency (SCID). However, adverse outcomes primarily due to histocompatibility differences between the donor and the patient are still of concern. Progress in genetic and molecular mechanisms, as well as new technology to insert DNA sequences in cell genomes has allowed the development of strategies to treat genetic diseases by correcting the gene defect in patients' cells. This technology is named gene therapy. Gene therapy approaches being developed for IEI are mediated by gene insertion, using a retroviral vector, or by gene editing, using a combination of a nuclease and a DNA template. After the unexpected occurrence of oncogenesis associated with the initial retroviral vector designs, significant advances have led to successful gene therapy clinical trials for three forms of SCID, which demonstrated the safety and efficacy of this approach. Active preclinical and clinical studies are ongoing for diverse IEI, including chronic granulomatous disease, leukocyte adhesion deficiency, severe congenital neutropenia, Wiskott-Aldrich syndrome, X-linked agammaglobulinemia and familial forms of hemophagocytic lymphohistiocytosis.