Gene therapy for inborn errors of immunity: past progress, current status and future directions

Abstract

Inborn errors of immunity (IEIs), also known as primary immunodeficiencies, are a group of rare inherited disorders that affect the immune system. They result in severe, opportunistic infections, severe autoimmune manifestations and a predisposition to malignancy. The only curative treatment for many years has been allogenic haematopoietic stem cell transplantation (alloHSCT). However, this requires the availability of a suitable donor and has risks of morbidity and mortality. Autologous gene therapy (GT) abrogates the immunological complications of alloHSCT and uses the patient’s own cells, removing the need for a donor. Preclinical proof-of-concept and clinical trials in humans have demonstrated that GT is safe and effective and can be used to correct a variety of IEIs. In this review, we outline the progress in developing GT for IEIs over the last four decades. We describe the gene editing technologies available to correct IEIs and their current applications. We also examine advances in GT development, the challenges to its application, and discuss future developments in the field, including emerging in vivo approaches.

Keywords

Gene therapy / inborn errors of immunity / primary immunodeficiency

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