Gene therapy of inherited immunodeficiencies

Abstract

Background: Primary immunodeficiencies (PID) are a group of inherited diseases that affect the development or activity of the immune system. In severe cases allogeneic haematopoietic stem cell transplantation has proved to be a successful curative modality but it is limited by toxicity and reduced efficacy in mismatched donor settings.

Objective: Gene therapy for PID has been developed as an alternative strategy and has entered the clinical arena. In this review we discuss the outcomes of recent gene therapy trials and some of the problems that remain to be tackled.

Methods: Results from clinical trials for X-linked severe combined immunodeficiency (SCID-X1), adenosine deaminase deficient SCID (ADA-SCID), and X-linked chronic granulomatous disease (X-CGD) are discussed. In addition, other conditions are highlighted such as the Wiskott Aldrich Syndrome (WAS) for which gene therapy has shown considerable promise in preclinical studies, and are currently being translated into novel clinical approaches.

Results/conclusion: Whilst these encouraging results demonstrate that gene therapy can be used successfully to treat monogenic PID, the occurrence of vector-related side effects has highlighted the need for accurate assessment of the associated risks and a requirement for improvements in vector design.